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Joensuu H, Miyashita H, George S, Sicklick J. Navigating Ongoing Challenges in GI Stromal Tumors. Am Soc Clin Oncol Educ Book 2025; 45:e473224. [PMID: 40393024 DOI: 10.1200/edbk-25-473224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/22/2025]
Abstract
GI stromal tumors (GISTs) are mesenchymal neoplasms with variable natural histories, originating in the GI tract, most commonly in the stomach. They are frequently characterized by KIT or platelet-derived growth factor receptor alpha (PDGFRA) oncogenic mutations. Surgical resection remains the cornerstone treatment for localized GISTs. Clinical trials have demonstrated the benefits of adjuvant imatinib in patients selected on the basis of recurrence risk and gene mutations, although the optimal duration of therapy is yet to be established. Some data suggest that longer durations of adjuvant imatinib (>3 years) may provide additional benefit, which is being investigated in ongoing trials. Management of imatinib-related adverse effects is essential during treatment, and longitudinal abdominal imaging is mandatory both during and after adjuvant therapy. Once GISTs are more advanced and unresectable, KIT- and PDGFRA-directed tyrosine kinase inhibitors (TKIs) become the key treatment in most patients with KIT mutation. Several TKIs have regulatory approval for advanced GISTs, but in most patients, resistance to TKIs eventually emerges, mainly from secondary resistance mutations in KIT. Each TKI has different coverage of oncogenic KIT mutations, suggested by preclinical and clinical findings, which has given rationale to an ongoing clinical trial that includes molecular selection as eligibility criteria. Furthermore, novel treatment approaches, from TKI combinations to an antibody-drug conjugate, are being investigated. Despite the significant advance in managing GISTs with KIT mutations, those without KIT or PDGFRA mutation, which consists of 10%-15% of patients with GIST, can be a clinical challenge in the advanced setting. These non-KIT/PDGFRA GISTs could be driven by genomic or epigenomic alterations in SDHx, NF1 mutations, and other genomic alterations. Non-KIT/PDGFRA GISTs are less responsive to currently available TKIs than GISTs driven by KIT/PDGFRA mutations, and each subset of non-KIT/PDGFRA GIST has distinctive biology and clinical features. Therefore, individualized, multidisciplinary, biology-based management and consideration for clinical trial enrollment are critical for non-KIT/PDGRFA GISTs.
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Affiliation(s)
- Heikki Joensuu
- Department of Oncology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | | | - Suzanne George
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Jason Sicklick
- Department of Surgery, University of California San Diego, San Diego, CA
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Nuñez Hernández I, Gómez Palmero C, Delgado JR, Nuño A, Sala González MÁ, González Ageitos A, Aguilar H, Ayala de Miguel P, Condori E, Díaz Beveridge R, Martínez García J, Marquina G, Varela-Pose V, Veas Rodríguez J, Serrano C. Evaluation of the effectiveness and safety of avapritinib in real-world Spanish cases with gastrointestinal stromal tumor and D842V-PDGFRA mutation. Oncologist 2025; 30:oyaf062. [PMID: 40349140 PMCID: PMC12065942 DOI: 10.1093/oncolo/oyaf062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Accepted: 03/05/2025] [Indexed: 05/14/2025] Open
Abstract
INTRODUCTION Gastrointestinal stromal tumors (GISTs) are the most common sarcoma subtype. Patients with unresectable or metastatic GISTs harboring the D842V mutation in the PDGFRA gene have a poor prognosis due to intrinsic resistance to imatinib and all other approved tyrosine kinase inhibitors. Avapritinib, targeting this mutation, is the first agent approved for patients with unresectable or metastatic GIST that have the PDGFRA D842V mutation. This study assesses the effectiveness and safety of avapritinib in real-world clinical scenarios involving Spanish patients with this mutation. MATERIALS AND METHODS The AVARWE study is a descriptive, retrospective, multicenter observational study of 21 patients treated with avapritinib across 13 Spanish centers from June 9, 2023, to December 18, 2023. Data collected included patient demographics, disease characteristics, treatment history, and response rates based on RECIST criteria. The main outcomes, progression-free survival (PFS) and overall survival (OS), were measured, with safety assessed through adverse events documentation according to CTCAE criteria. RESULTS Median PFS 35.6 was months and median OS was 42.2 months, with survival rates at 1, 5, and 3 years demonstrating avapritinib effectiveness. The objective response rate was 76.2% for partial response and 4.8% for complete response. Avapritinib enabled surgical intervention in previously unresectable cases and was generally well-tolerated, with manageable adverse events. CONCLUSION Avapritinib extends PFS and OS among patients with PDGFRA D842V-mutant GIST in real-world practice, mirroring pivotal trial outcomes. Its substantial activity supports its use as a first-line therapy for this subgroup. The manageable safety profile reinforces avapritinib viability for routine use. Given the rarity of these cases, it is advised to consult sarcoma-expert units.
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Affiliation(s)
- Isaac Nuñez Hernández
- Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Ctra. Gral. del Rosario, 145, 38010, Spain
- Fundación Investigación del cáncer en Canarias | FICIC, Av. Alcalde Díaz Saavedra Navarro, 31, 35001 Las Palmas de Gran Canaria, Las Palmas, Spain
| | - Cristina Gómez Palmero
- Hospital Universitario de Toledo, Toledo, Av. del Río Guadiana, 45007, Spain
- Hospital Universitario Vall d’Hebron, Pg. de la Vall d'Hebron, 119, Horta-Guinardó, 08035, Barcelona, Spain
| | - Juan Ramón Delgado
- Hospital Universitario Virgen de las Nieves (HUVN), Av. de las Fuerzas Armadas, 2, Beiro, 18014 Granada, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, Av. de Madrid, 15, Beiro, 18012 Granada, Spain
| | - Ana Nuño
- Hospital Obispo Polanco, Av. Ruiz Jarabo, s/n, 44002, Teruel, Spain
| | | | | | - Héctor Aguilar
- Fundación Instituto Valenciano de Oncología, Carrer del Professor Beltrán Báguena, 8, Campanar, 46009, Valencia, Spain
| | - Pablo Ayala de Miguel
- Complejo Hospitalario Universitario de Cáceres, Av. de la Universidad, 75, Norte, 10004 Cáceres, Spain
| | - Elizabeth Condori
- Hospital Santa Bárbara de Soria, Pº de Santa Bárbara, s/n, 42005, Soria, Spain
| | - Roberto Díaz Beveridge
- Hospital Universitari i Politècnic La Fe, Avinguda de Fernando Abril Martorell, 106, Quatre Carreres, 46026, Valencia, Spain
| | - Jerónimo Martínez García
- HCU Virgen de la Arrixaca, Ctra. Madrid-Cartagena, s/n, 30120 El Palmar, Murcia, Spain
- Grupo Investigación en IMIB-Murcia, Ctra. Madrid-Cartagena, s/n, 30120 El Palmar,Spain
| | - Gloria Marquina
- Department of Medical Oncology, Hospital Clínico San Carlos, Department of Medicine, School of Medicine, Universidad Complutense de Madrid (UCM), Instituto de Investigación Sanitaria (IdISSC), Calle del Prof Martín Lagos, S/N, Moncloa - Aravaca, 28040, Madrid, Spain
| | - Vanesa Varela-Pose
- University Hospital of Santiago de Compostela (SERGAS), Rúa da Choupana, s/n, 15706, Santiago de Compostela, Spain
- Translational Medical Oncology Group (Oncomet), Rúa da Choupana, s/n, 15706, Santiago de Compostela, Spain
- Health Research Institute of Santiago de Compostela (IDIS), Rúa da Choupana, s/n, 15706, Santiago de Compostela, Spain
| | - Joel Veas Rodríguez
- Hospital Arnau de Vilanova de Lleida, Av. Alcalde Rovira Roure, 80, 25198, Lleida, Spain
- Musgrove Park Hospital, Somerset NHS Foundation Trust, Parkfield Dr, Taunton TA1 5DA, Reino Unido
| | - César Serrano
- Hospital Universitario Vall d’Hebron, Pg. de la Vall d'Hebron, 119, Horta-Guinardó, 08035, Barcelona, Spain
- Vall d’Hebron Institute of Oncology (VHIO), Carrer de Natzaret 115-117, 08035 Barcelona, Spain
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Mayr L, Neyazi S, Schwark K, Trissal M, Beck A, Labelle J, Eder SK, Weiler-Wichtl L, Marques JG, de Biagi-Junior CAO, Lo Cascio C, Chapman O, Sridhar S, Kenkre R, Dutta A, Wang S, Wang J, Hack O, Nascimento A, Nguyen CM, Castellani S, Rozowsky JS, Groves A, Panditharatna E, Cruzeiro GAV, Haase RD, Tabatabai K, Madlener S, Wadden J, Adam T, Kong S, Miclea M, Patel T, Bruckner K, Senfter D, Lämmerer A, Supko J, Guntner AS, Palova H, Neradil J, Stepien N, Lötsch-Gojo D, Berger W, Leiss U, Rosenmayr V, Dorfer C, Dieckmann K, Peyrl A, Azizi AA, Baumgartner A, Slaby O, Pokorna P, Clark LM, Cameron A, Nguyen QD, Wakimoto H, Dubois F, Greenwald NF, Bandopadhayay P, Beroukhim R, Ligon K, Kramm C, Bronsema A, Bailey S, Stucklin AG, Mueller S, Skrypek M, Martinez N, Bowers DC, Jones DTW, Jones C, Jäger N, Sterba J, Müllauer L, Haberler C, Kumar-Sinha C, Chinnaiyan A, Mody R, Chavez L, Furtner J, Koschmann C, Gojo J, Filbin MG. Effective targeting of PDGFRA-altered high-grade glioma with avapritinib. Cancer Cell 2025; 43:740-756.e8. [PMID: 40086436 PMCID: PMC12121847 DOI: 10.1016/j.ccell.2025.02.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 11/27/2024] [Accepted: 02/12/2025] [Indexed: 03/16/2025]
Abstract
PDGFRA is crucial to tumorigenesis and frequently genomically altered in high-grade glioma (HGG). In a comprehensive dataset of pediatric HGG (n = 261), we detect PDGFRA mutations and/or amplifications in 15% of cases, suggesting PDGFRA as a therapeutic target. We reveal that the PDGFRA/KIT inhibitor avapritinib shows (1) selectivity for PDGFRA inhibition, (2) distinct patterns of subcellular effects, (3) in vitro and in vivo activity in patient-derived HGG models, and (4) effective blood-brain barrier penetration in mice and humans. Furthermore, we report preliminary clinical real-world experience using avapritinib in pediatric and young adult patients with predominantly recurrent/refractory PDGFRA-altered HGG (n = 8). Our early data demonstrate that avapritinib is well tolerated and results in radiographic response in 3/7 cases, suggesting a potential role for avapritinib in the treatment of HGG with specific PDGFRA alterations. Overall, these translational results underscore the therapeutic potential of PDGFRA inhibition with avapritinib in HGG.
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Affiliation(s)
- Lisa Mayr
- Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02215, USA; Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
| | - Sina Neyazi
- Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02215, USA
| | - Kallen Schwark
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Maria Trissal
- Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02215, USA
| | - Alexander Beck
- Center for Neuropathology and Prion Research, Ludwig Maximilians University Munich, Faculty of Medicine, Muenchen, 80539 Bayern, Germany
| | - Jenna Labelle
- Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02215, USA
| | - Sebastian K Eder
- Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02215, USA; St. Anna Children's Hospital, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna and St. Anna Children's Cancer Research Institute (CCRI), 1090 Vienna, Austria
| | - Liesa Weiler-Wichtl
- Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
| | - Joana G Marques
- Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02215, USA
| | - Carlos A O de Biagi-Junior
- Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02215, USA
| | - Costanza Lo Cascio
- Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02215, USA
| | - Owen Chapman
- Sanford Burnham Prebys Medical Discovery Institute, San Diego, CA 92037, USA
| | - Sunita Sridhar
- Sanford Burnham Prebys Medical Discovery Institute, San Diego, CA 92037, USA
| | - Rishaan Kenkre
- Sanford Burnham Prebys Medical Discovery Institute, San Diego, CA 92037, USA
| | - Aditi Dutta
- Sanford Burnham Prebys Medical Discovery Institute, San Diego, CA 92037, USA
| | - Shanqing Wang
- Sanford Burnham Prebys Medical Discovery Institute, San Diego, CA 92037, USA
| | - Jessica Wang
- Sanford Burnham Prebys Medical Discovery Institute, San Diego, CA 92037, USA
| | - Olivia Hack
- Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02215, USA
| | - Andrezza Nascimento
- Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02215, USA
| | - Cuong M Nguyen
- Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02215, USA
| | - Sophia Castellani
- Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02215, USA
| | - Jacob S Rozowsky
- Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02215, USA
| | - Andrew Groves
- Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02215, USA
| | - Eshini Panditharatna
- Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02215, USA
| | - Gustavo Alencastro Veiga Cruzeiro
- Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02215, USA
| | - Rebecca D Haase
- Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02215, USA
| | - Kuscha Tabatabai
- Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02215, USA
| | - Sibylle Madlener
- Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
| | - Jack Wadden
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Tiffany Adam
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Seongbae Kong
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Madeline Miclea
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Tirth Patel
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Katharina Bruckner
- Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria; Department of Neurosurgery, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
| | - Daniel Senfter
- Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
| | - Anna Lämmerer
- Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria; Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria; Research Cluster "Translational Cancer Therapy Research", University of Vienna and Medical University of Vienna, 1090 Vienna, Austria
| | - Jeffrey Supko
- Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Armin S Guntner
- Institute for Analytical and General Chemistry, Johannes Kepler University, 4040 Linz, Austria
| | - Hana Palova
- Central European Institute of Technology, Masaryk University, 60177 Brno, Czech Republic
| | - Jakub Neradil
- Department of Experimental Biology, Faculty of Science, Masaryk University, 61137 Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
| | - Natalia Stepien
- Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
| | - Daniela Lötsch-Gojo
- Department of Neurosurgery, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
| | - Walter Berger
- Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria; Research Cluster "Translational Cancer Therapy Research", University of Vienna and Medical University of Vienna, 1090 Vienna, Austria
| | - Ulrike Leiss
- Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
| | - Verena Rosenmayr
- Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
| | - Christian Dorfer
- Department of Neurosurgery, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
| | - Karin Dieckmann
- Department of Radiotherapy, Medical University of Vienna, 1090 Vienna, Austria
| | - Andreas Peyrl
- Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
| | - Amedeo A Azizi
- Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
| | - Alicia Baumgartner
- Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02215, USA; Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria
| | - Ondrej Slaby
- Central European Institute of Technology, Masaryk University, 60177 Brno, Czech Republic; Department of Biology, Faculty of Medicine, Masaryk University, 62500 Brno, Czech Republic
| | - Petra Pokorna
- Central European Institute of Technology, Masaryk University, 60177 Brno, Czech Republic
| | - Louise M Clark
- Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02210, USA
| | - Amy Cameron
- Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02210, USA
| | - Quang-De Nguyen
- Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02210, USA
| | - Hiroaki Wakimoto
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA
| | - Frank Dubois
- Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02215, USA
| | - Noah F Greenwald
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Cancer Biology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02115, USA
| | - Pratiti Bandopadhayay
- Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02215, USA
| | - Rameen Beroukhim
- Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Cancer Biology and Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA 02115, USA
| | - Keith Ligon
- Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02215, USA
| | - Christof Kramm
- Division of Pediatric Hematology and Oncology, University Medical Center Göttingen, 37099 Göttingen, Germany
| | - Annika Bronsema
- Clinic of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
| | - Simon Bailey
- Great North Childrens Hospital and Newcastle University, Newcastle upon Tyne, UK; Newcastle Hospitals NHS Foundation Trust, NE1 4LP Newcastle, UK
| | - Ana Guerreiro Stucklin
- Department of Oncology and Children's Research Center, University Children's Hospital Zurich, 8008 Zurich, Switzerland
| | - Sabine Mueller
- Departments of Pediatrics, Neurology, and Neurological Surgery, University of California San Francisco, San Francisco, CA 94143, USA
| | - Mary Skrypek
- Department of Pediatric Hematology-Oncology, Children's Minnesota, Minneapolis, MN 55404, USA
| | - Nina Martinez
- Department of Neurology & Neurological Surgery, Jefferson University, Philadelphia, PA 19107, USA
| | - Daniel C Bowers
- Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - David T W Jones
- Hopp Children's Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany; Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Chris Jones
- Division of Molecular Pathology, Institute of Cancer Research, SM2 5NG London, UK
| | - Natalie Jäger
- Hopp Children's Cancer Center Heidelberg (KiTZ) & Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Jaroslav Sterba
- Department of Pediatric Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, 662630 Brno, Czech Republic
| | - Leonhard Müllauer
- Department of Pathology, Medical University of Vienna, 1090 Vienna, Austria
| | - Christine Haberler
- Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria
| | - Chandan Kumar-Sinha
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Arul Chinnaiyan
- Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Rajen Mody
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USA
| | - Lukas Chavez
- Sanford Burnham Prebys Medical Discovery Institute, San Diego, CA 92037, USA
| | - Julia Furtner
- Division of Neuroradiology and Musculoskeletal Radiology, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, 1090 Vienna, Austria; Research Center of Medical Image Analysis and Artificial Intelligence, Danube Private University, 3500 Krems an der Donau, Austria
| | - Carl Koschmann
- Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
| | - Johannes Gojo
- Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria.
| | - Mariella G Filbin
- Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorder Center and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
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Liu Y, Li XF. Characteristics and therapeutic strategies for familial gastrointestinal stromal tumors. World J Gastrointest Oncol 2025; 17:100463. [PMID: 40092960 PMCID: PMC11866256 DOI: 10.4251/wjgo.v17.i3.100463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Revised: 11/04/2024] [Accepted: 12/16/2024] [Indexed: 02/14/2025] Open
Abstract
This editorial discusses Wang et al's article on familial gastrointestinal stromal tumors (GISTs). We read with great interest this article concerning the diagnosis, treatment, and post-treatment management of patients with familial GISTs. The actual incidence of GISTs may be underestimated due to diagnostic limitations and the long-term low-risk behavior of some GISTs. The molecular landscape of GISTs is primarily driven by mutations in the KIT and platelet-derived growth factor receptor alpha (PDGFRA) genes. A subset of GISTs without these mutations known as wild-type GISTs, may harbor other rare mutations, impacting their response to targeted therapies. Clinically, patients with GISTs present with non-specific symptoms, often leading to delayed diagnosis. Genetic predispositions in familial GISTs provide insights into the genetic architecture and extragastrointestinal manifestations of GISTs. Management has evolved from surgical interventions to molecular-based therapies using tyrosine kinase inhibitors. The management of GISTs, especially in familial cases, requires a multidisciplinary approach. Cases of different gene mutations were reported in the same family, suggesting that incorporating genetic testing into routine clinical practice is crucial for the early identification of high-risk individuals and the implementation of tailored surveillance programs.
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Affiliation(s)
- Yuan Liu
- Department of Gastroenterology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, Guangdong Province, China
| | - Xiao-Feng Li
- Department of Gastroenterology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, Guangdong Province, China
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Wei JR, Lu MY, Wei TH, Fleishman JS, Yu H, Chen XL, Kong XT, Sun SL, Li NG, Yang Y, Ni HW. Overcoming cancer therapy resistance: From drug innovation to therapeutics. Drug Resist Updat 2025; 81:101229. [PMID: 40081221 DOI: 10.1016/j.drup.2025.101229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 02/18/2025] [Accepted: 03/03/2025] [Indexed: 03/15/2025]
Abstract
One of the major limitations of cancer therapy is the emergence of drug resistance. This review amis to provide a focused analysis of the multifactorial mechanisms underlying therapy resistance,with an emphasis on actionable insights for developing novel therapeutic strategies. It concisely outlines key factors contributing to therapy resistance, including drug delivery barriers, cancer stem cells (CSCs), epithelial-mesenchymal transition (EMT), cancer heterogeneity, tumor microenvironment (TME), genetic mutations, and alterlations in gene expression. Additionally, we explore how tumors evade targeted therapies through pathway-specific mechanisms that restore disrupted signaling pathways. The review critically evaluates innovative strategies designed to sensitize resistant tumor cells, such as targeted protein dedgradation, antibody-drug conjugates, structure-based drug design, allosteric drugs, multitarget drugs, nanomedicine and others We also highlight the importance of understanding the pharmacological actions of these agents and their integration into treatment regimens. By synthesizing current knowledge and identifying gaps in our understanding, this review aims to guide future research and improve patient outcomes in cancer therapy.
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Affiliation(s)
- Jin-Rui Wei
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing 210029, China; The First Clinical College of Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Meng-Yi Lu
- Department of Biostatistics, School of Public Health, Nanjing Medical University, Nanjing 210029, China
| | - Tian-Hua Wei
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Joshua S Fleishman
- College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA
| | - Hui Yu
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing 210029, China
| | - Xiao-Li Chen
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing 210029, China
| | - Xiang-Tu Kong
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing 210029, China
| | - Shan-Liang Sun
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing 210023, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China.
| | - Nian-Guang Li
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Ye Yang
- National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Jiangsu Key Laboratory for High Technology Research of TCM Formulae, Nanjing University of Chinese Medicine, Nanjing 210023, China; School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
| | - Hai-Wen Ni
- Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Provincial Hospital of Traditional Chinese Medicine, Nanjing 210029, China.
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6
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Strauss G, George S. Gastrointestinal Stromal Tumors. Curr Oncol Rep 2025; 27:312-321. [PMID: 39985704 DOI: 10.1007/s11912-025-01636-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/07/2025] [Indexed: 02/24/2025]
Abstract
PURPOSE OF REVIEW This review aims to outline the current understanding of the molecular drivers and treatment paradigms of gastrointestinal stromal tumors, with a focus on recent developments in treatment in the advanced disease setting. RECENT FINDINGS There have been recent advancements in our understanding of the molecular biology of gastrointestinal stromal tumors, including the identification of new genetic drivers and complex resistance mechanisms. We review the most recent findings in these areas, focusing on how new research insights are reshaping treatment strategies. Recent advancements in our understanding of the biology and treatment of GIST are paving the way for more personalized and effective therapeutic options. As knowledge of rare molecular subtypes, resistance mechanisms, and novel genomic techniques grows, new approaches are emerging in an effort to improve patient outcomes.
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Affiliation(s)
- Gal Strauss
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Suzanne George
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
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7
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Boulouadnine B, Filser M, Leducq C, Losole T, Bies J, Smetsers S, Kouwenberg D, de Lange I, Mensenkamp A, Kordes UR, Minard-Colin V, Orbach D, Brichard B, de Krijger R, Masliah-Planchon J, Demoulin JB. A germline PDGFRB splice site variant associated with infantile myofibromatosis and resistance to imatinib. Genet Med 2025; 27:101334. [PMID: 39580648 DOI: 10.1016/j.gim.2024.101334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 11/15/2024] [Accepted: 11/15/2024] [Indexed: 11/26/2024] Open
Abstract
PURPOSE Infantile myofibromatosis is characterized by the development of myofibroblastic tumors in young children. In most cases, the disease is caused by somatic gain-of-function variants in platelet-derived growth factor (PDGF) receptor beta (PDGFRB). Here, we reported a novel germline intronic PDGFRB variant, c.2905-8G>A, in 6 unrelated infants with multifocal myofibromatosis and their relatives. METHODS We performed constitutional and tumor DNA and RNA sequencing to identify novel variants, which were subsequently characterized in cellular assays. RESULTS All patients had multiple skin nodules, 4 had bone lesions, and 2 had aggressive disease with bowel obstruction. The c.2905-8G>A substitution creates an alternative acceptor splice site in intron 21, inserting 2 codons in the PDGFRB transcript. Functional studies revealed that the splice change induced a partial loss of function, contrasting with previously described variants. In 4 tumor samples, we identified a second somatic hit at position Asp850 in PDGFRB exon 18, triggering constitutive receptor activation and resistance to imatinib. In addition to vinblastine and methotrexate, 2 patients received imatinib without objective response. One of them switched to dasatinib with concomitant improvement. CONCLUSION This splice-site PDGFRB variant favors the development of myofibroma, featuring an acquired oncogenic variant in the same gene and resistance to targeted therapy.
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Affiliation(s)
| | | | - Camille Leducq
- De Duve Institute, University of Louvain, Brussels, Belgium
| | - Taylor Losole
- Department of Pediatric Hematology/Oncology, University of Nebraska Medical Center, Children's Nebraska, Omaha, NE
| | - Joshua Bies
- Department of Pediatric Hematology/Oncology, University of Nebraska Medical Center, Children's Nebraska, Omaha, NE
| | | | - Dorus Kouwenberg
- Princess Maxima Center for pediatric oncology, Utrecht, The Netherlands
| | - Iris de Lange
- Department of Genetics, University Medical Center Utrecht, Utrecht University, The Netherlands
| | - Arjen Mensenkamp
- Diagnostic laboratory of the Radboud University Medical Center, Nijmegen, The Netherlands
| | - Uwe Richard Kordes
- Department of Paediatric Haematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Véronique Minard-Colin
- Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France
| | - Daniel Orbach
- SIREDO Oncology Center (Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer), PSL University, Institut Curie, Paris, France
| | - Bénédicte Brichard
- Department of Pediatric Hematology and Oncology, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Ronald de Krijger
- Princess Maxima Center for pediatric oncology, Utrecht, The Netherlands; Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
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8
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Mao W, Jiang J, Xia Y, Zhang L. Analysis of postmarketing neuropsychiatric adverse events of avapritinib based on the FDA adverse event reporting system. Sci Rep 2025; 15:3108. [PMID: 39856211 PMCID: PMC11760955 DOI: 10.1038/s41598-025-86959-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 01/15/2025] [Indexed: 01/30/2025] Open
Abstract
Neuropsychiatric adverse events (AEs) significantly impact the quality of life of patients using avapritinib. However, the majority of current data comes from pre-marketing, with limited real-world studies. Our research aimed to explore post-marketing data of avapritinib. We evaluated the signals of avapritinib-related neuropsychiatric AEs by data mining using the FDA Adverse Event Reporting System (FAERS). Reporting odds ratio (ROR) and information component (IC) were employed to quantify the signals from the first quarter of 2020 through the fourth quarter of 2023. Subsequently, stratified analyses were conducted to further explore the effect of different stratification schemes on the association between avapritinib and neuropsychiatric AEs. Finally, a combination medication analysis was conducted to explore the impact of the co-administration of neuropsychiatric AEs. A total of 2029 neuropsychiatric AEs were reported, and 49 signals were detected, of which 5 were determined to be new signals. Avapritinib was significantly associated with the occurrence of neuropsychiatric AEs (ROR: 1.52, 95% CI: 1.44-1.61; IC: 0.43, IC025: 0.35). The stratified analysis found that gender, age and eight preferred terms (PTs), including cerebral haemorrhage, may affect the severity of AEs. Combination medication analysis showed that combining avapritinib with 19 other medications, including prochlorperazine, may increase the risk of neuropsychiatric AEs. The median time-to-onset (TTO) of avapritinib-related neuropsychiatric AEs was 32 (interquartile range [IQR] 2-200) days, with about 65% of cases occurring within the first three months of treatment. An increase in the signal for neuropsychiatric AEs was identified in post-marketing studies of avapritinib. Clinicians are advised to remain vigilant for such events, particularly during the initial stages of treatment with avapritinib.
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Affiliation(s)
- Wei Mao
- Department of Pharmacy, Nanan People's Hospital of Chongqing, Chongqing, China
| | - Junyan Jiang
- Department of Gastroenterology, Nanan People's Hospital of Chongqing, Chongqing, China
| | - Yanping Xia
- Department of Pharmacy, Nanan People's Hospital of Chongqing, Chongqing, China
| | - Lin Zhang
- Department of Pharmacy, The First Affiliated Hospital of Army Medical University, Chongqing, China.
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9
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Judson I, Jones RL, Wong NACS, Dileo P, Bulusu R, Smith M, Almond M. Gastrointestinal stromal tumour (GIST): British Sarcoma Group clinical practice guidelines. Br J Cancer 2025; 132:1-10. [PMID: 38840030 PMCID: PMC11723931 DOI: 10.1038/s41416-024-02672-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 03/21/2024] [Accepted: 03/25/2024] [Indexed: 06/07/2024] Open
Abstract
BACKGROUND British Sarcoma Group guidelines for the management of GIST were initially informed by those published by the European Society of Clinical Oncology. This update was written by a group of experts to includes a discussion of the highlight improvements in our knowledge of the disease and recent treatment developments. The guidelines include sections on Incidence, Aetiology, Diagnosis, including risk assessment, Treatment and Follow-up. METHODS A careful review of the literature was performed to ensure that wherever possible recommendations are supported by the results of clinical trials or substantive retrospective reports. Areas of uncertainty are indicated appropriately. CONCLUSION Guidelines represent a consensus view of current best clinical practice. Where appropriate, key recommendations are given and the levels of evidence and strength of recommendation gradings are those used by the European Society for Medical Oncology (ESMO).
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Affiliation(s)
- Ian Judson
- The Institute of Cancer Research, London, UK.
| | | | | | | | | | - Myles Smith
- Royal Marsden NHS Foundation Trust, London, UK
| | - Max Almond
- Birmingham University Hospitals, Birmingham, UK
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10
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Blay JY, Devin Q, Duffaud F, Toulmonde M, Firmin N, Collard O, Bompas E, Verret B, Ray-Coquard I, Salas S, Henon C, Honoré C, Brahmi M, Dufresne A, Pracht M, Hervieu A, Penel N, Bertucci F, Rios M, Saada-Bouzid E, Soibinet P, Perol D, Chabaud S, Italiano A, Cesne AL. Discontinuation versus continuation of imatinib in patients with advanced gastrointestinal stromal tumours (BFR14): exploratory long-term follow-up of an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol 2024; 25:1163-1175. [PMID: 39127063 DOI: 10.1016/s1470-2045(24)00318-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 05/09/2024] [Accepted: 05/23/2024] [Indexed: 08/12/2024]
Abstract
BACKGROUND The long-term impact of tyrosine kinase inhibitor (TKI) discontinuation on resistance and survival in patients with advanced gastrointestinal stromal tumours (GIST) is unclear. We report the exploratory long-term outcomes of patients with advanced GIST stopping imatinib in the BFR14 trial. METHODS BFR14, an open-label, randomised, phase 3 trial, was done in 17 comprehensive cancer centres or hospitals across France. Patients with advanced GIST aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-3, no previous treatment with imatinib, and no previous malignancy were eligible. Patients were treated with oral imatinib 400 mg daily. Patients with a complete or partial response, or stable disease, according to Response Evaluation Criteria in Solid Tumours (1.0) at 1 year, 3 years, and 5 years from the start of treatment were randomly assigned (1:1) to treatment discontinuation until progression (interruption group) or treatment continuation until progression (continuation group). Randomisation was done centrally with computer-generated permuted blocks of two and six patients stratified by participating centre and presence or absence of residual disease on CT scan. The primary endpoint was progression-free survival. Secondary endpoints included time to imatinib resistance and overall survival. Analyses were conducted on an intention-to-treat basis in all randomly assigned patients who were not lost to follow-up. This trial is registered with ClinicalTrial.gov, NCT00367861. FINDINGS Between May 12, 2003, and March 16, 2004, after 1 year of imatinib, 32 patients were randomly assigned to the interruption group and 26 to the continuation group. Between June 13, 2005, and May 30, 2007, after 3 years of imatinib, 25 patients were randomly assigned to the interruption group and 25 to the continuation group. Between Nov 9, 2007, and July 12, 2010, after 5 years of imatinib, 14 patients were randomly assigned to the interruption group and 13 to the continuation group. Median follow-up was 235·2 months (IQR 128·8-236·6) after the 1-year randomisation, 200·9 months (190·2-208·4) after the 3-year randomisation, and 164·5 months (134·4-176·4) after the 5-year randomisation. Median progression-free survival in the interruption group versus the continuation group after 1 year of imatinib was 6·1 months (95% CI 2·5-10·1) versus 27·8 months (19·5-37·9; hazard ratio [HR] 0·36 [95% CI 0·20-0·64], log-rank p=0·0003), after 3 years of imatinib was 7·0 months (3·5-11·7) versus 67·0 months (48·8-85·6; 0·15 [0·07-0·32], log-rank p<0·0001), and after 5 years of imatinib was 12·0 months (9·0-16·6) versus not reached (NR; NR-NR; 0·13 [0·03-0·58], log-rank p=0·0016). The median time to imatinib resistance after 1 year of imatinib was 28·7 months (95% CI 18·1-39·1) versus 90·6 months (25·3-156·1; HR 0·93 [95% CI 0·51-1·71], log-rank p=0·82), after 3 years was 66·2 months (43·0-89·6) versus 127·3 months (15·0-239·7; 0·35 [0·17-0·72, log-rank p=0·0028), and after 5 years was 58·6 months (0·0-167·4) versus NR (NR-NR; 0·24 [0·05-1·12], log-rank p=0·049). Median overall survival after 1 year of imatinib was 56·0 months (95% CI 30·3-82·9) versus 105·0 months (20·6-189·6; HR 0·84 [95% CI 0·46-1·54], log-rank p=0·57), after 3 years was 104·0 months (90·7-118·7) versus 134·0 months (89·7-178·3; 0·40 [0·20-0·82], log-rank p=0·0096), and after 5 years was NR (NR-NR) versus 110·4 months (82·7-154·1; 1·28 [0·41-3·99]; log-rank p=0·67), INTERPRETATION: Imatinib interruption in patients with GIST without progressive disease is not recommended. Imatinib interruption in non-progressing patients with GIST was associated with rapid progression, faster resistance to imatinib, and shorter overall survival in the long-term follow-up when compared with imatinib continuation in patients after 3 years and 5 years of imatinib. FUNDING Centre Léon Bérard, INCa, CONTICANET, Ligue Contre le Cancer, and Novartis.
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Affiliation(s)
- Jean-Yves Blay
- Centre Léon Bérard, Lyon, France; Université Claude Bernard Lyon I, Lyon, France; Centre de Recherche en Cancérologie de Lyon, Lyon, France.
| | - Quentin Devin
- Centre Léon Bérard, Lyon, France; Université Claude Bernard Lyon I, Lyon, France; Centre de Recherche en Cancérologie de Lyon, Lyon, France
| | | | | | - Nelly Firmin
- Institut de Cancérologi Val d'Aurelle, Montpellier, France
| | - Olivier Collard
- Centre Léon Bérard, Lyon, France; Université Claude Bernard Lyon I, Lyon, France; Centre de Recherche en Cancérologie de Lyon, Lyon, France; Hopitaux Privés de la Loire, St Etienne, France
| | | | - Benjamin Verret
- Hopitaux Privés de la Loire, St Etienne, France; Institut Gustave Roussy, Villejuif, France
| | - Isabelle Ray-Coquard
- Centre Léon Bérard, Lyon, France; Université Claude Bernard Lyon I, Lyon, France; Centre de Recherche en Cancérologie de Lyon, Lyon, France
| | | | - Clemence Henon
- Hopitaux Privés de la Loire, St Etienne, France; Institut Gustave Roussy, Villejuif, France
| | | | - Mehdi Brahmi
- Centre Léon Bérard, Lyon, France; Université Claude Bernard Lyon I, Lyon, France; Centre de Recherche en Cancérologie de Lyon, Lyon, France
| | - Armelle Dufresne
- Centre Léon Bérard, Lyon, France; Université Claude Bernard Lyon I, Lyon, France; Centre de Recherche en Cancérologie de Lyon, Lyon, France
| | | | | | | | | | - Maria Rios
- Institut de Cancérologie de Lorraine-Alexis Vautrin, Vandoeuvre-lès-Nancy, France
| | | | | | - David Perol
- Centre Léon Bérard, Lyon, France; Centre de Recherche en Cancérologie de Lyon, Lyon, France; Direction Recherche Clinique et Innovation, Lyon, France
| | - Sylvie Chabaud
- Centre Léon Bérard, Lyon, France; Centre de Recherche en Cancérologie de Lyon, Lyon, France; Direction Recherche Clinique et Innovation, Lyon, France
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11
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Popoiu TA, Pîrvu CA, Popoiu CM, Iacob ER, Talpai T, Voinea A, Albu RS, Tãban S, Bãlãnoiu LM, Pantea S. Gastrointestinal Stromal Tumors (GISTs) in Pediatric Patients: A Case Report and Literature Review. CHILDREN (BASEL, SWITZERLAND) 2024; 11:1040. [PMID: 39334573 PMCID: PMC11429550 DOI: 10.3390/children11091040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 08/18/2024] [Accepted: 08/23/2024] [Indexed: 09/30/2024]
Abstract
Gastrointestinal stromal tumors (GISTs) are rare mesenchymal neoplasms that primarily affect adults, with pediatric cases constituting only 0.5-2.7% of the total. Pediatric GISTs present unique clinical, genetic, and pathological features that distinguish them from adult cases. This literature review aims to elucidate these differences, emphasizing diagnostic and therapeutic challenges. We discuss the resistance of pediatric GISTs to conventional chemotherapy and highlight the importance of surgical intervention, especially in emergency situations involving intra-abdominal bleeding. The review also explores the molecular characteristics of pediatric GISTs, including rare mutations such as quadruple-negative wild-type GIST with an FGF3 gene gain mutation. To illustrate these points, we conclude with a case from our clinic involving a 15-year-old female with multiple CD117-positive gastric GISTs and a quadruple-negative wild-type genetic profile who required urgent surgical intervention following a failed tumor embolization. This case underscores the critical need for early diagnosis and individualized therapeutic strategies combining oncologic and surgical care to improve outcomes in pediatric GIST patients.
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Affiliation(s)
- Tudor-Alexandru Popoiu
- Department of General Surgery, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
- Department III of Functional Sciences, Discipline of Medical Informatics and Biostatistics, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Cãtãlin-Alexandru Pîrvu
- Department of General Surgery, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Cãlin-Marius Popoiu
- Department of Pediatric Surgery, "Victor Babes" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Emil Radu Iacob
- Department of Pediatric Surgery, "Victor Babes" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Tamas Talpai
- Department of General Surgery, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Amalia Voinea
- Department of General Surgery, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Rãzvan-Sorin Albu
- Department of General Surgery, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Sorina Tãban
- Department of Pathology, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Larisa-Mihaela Bãlãnoiu
- Department of General Surgery, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Stelian Pantea
- Department of General Surgery, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
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12
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Ganzon R, Chen W, Tinoco G. First Description of the Clinical Activity of Avapritinib in Sporadic Mesenteric Desmoid Tumor. Case Rep Oncol Med 2024; 2024:8684418. [PMID: 39135981 PMCID: PMC11319063 DOI: 10.1155/2024/8684418] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 06/17/2024] [Accepted: 07/04/2024] [Indexed: 08/15/2024] Open
Abstract
Desmoid tumors (DTs) are rare and locally aggressive with a high rate of local recurrence even with optimal surgical resection. Systemic treatments are often utilized for desmoid cases with high risk of surgical morbidity or for local and symptomatic control of recurrent disease. However, the systemic treatment options for DTs are limited with limited responses. Avapritinib is a tyrosine kinase inhibitor (TKI) approved in 2020 for adults with unresectable or metastatic gastrointestinal (GI) stromal tumors (GISTs) harboring a platelet-derived growth factor receptor alpha (PDGFRA) Exon 18 mutation, including D842V mutations. In this case report, we describe a 55-year-old man with a history of D842V-mutant gastric GIST who presented several years after complete resection of the GIST with an enlarging soft tissue mass in the small intestine. After a nondiagnostic biopsy, the patient was started on avapritinib due to concerns for recurrent D842V-mutant GIST. The tumor had a partial response to treatment by RECIST 1.1 criteria, and the patient underwent surgical resection. The final pathology report revealed a sporadic DT. To our knowledge, this is the first known description of the activity of avapritinib in the treatment of a sporadic mesenteric DT, which is relevant given the limited treatment options for patients with this diagnosis. This clinical finding may be worth exploring in a dedicated clinical trial.
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Affiliation(s)
- Rebecca Ganzon
- Division of Medical OncologyThe Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, Ohio, USA
| | - Wei Chen
- Department of PathologyThe Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, Ohio, USA
| | - Gabriel Tinoco
- Division of Medical OncologyThe Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, Ohio, USA
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13
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Beecroft JR, Brar S, Feng X, Hamilton T, Han-Lee C, Henning JW, Josephy PD, Khalili K, Ko YJ, Lemieux C, Liu DM, MacDonald DB, Noujaim J, Pollett A, Salawu A, Saleh R, Smrke A, Warren BE, Zbuk K, Razak AA. Pan-Canadian consensus recommendations for GIST management in high- and low-throughput centres across Canada. Ther Adv Med Oncol 2024; 16:17588359241266179. [PMID: 39386314 PMCID: PMC11461906 DOI: 10.1177/17588359241266179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 06/18/2024] [Indexed: 10/12/2024] Open
Abstract
Gastrointestinal stromal tumours (GISTs) are mesenchymal tumours that originate from the interstitial cells of Cajal. GISTs are mainly driven by gain-of-function mutations in receptor tyrosine kinase or platelet-derived growth factor receptor alpha. Surgical resection is the only curative treatment for localized tumours and all currently approved medical GIST treatments are based on orally available tyrosine kinase inhibitors. Recent discoveries in the molecular and clinical features of GISTs have greatly impacted GIST management. Due to the provincially rather than nationally administered Canadian healthcare system, there have been inconsistencies in the treatment of GISTs across the country. Therefore, guidance on the latest knowledge, clinical management and treatment of GIST is needed to standardize the approach to GIST management nationwide. To establish pan-Canadian guidance, provide up-to-date data and harmonize the clinical practice of GIST management in high- and low-throughput centres across Canada; a panel of 20 physicians with extensive clinical experience in GIST management reviewed relevant literature. This included radiologists, pathologists, interventional radiologists, surgeons and medical oncologists across Canada. The structured literature focused on seven key domains: molecular profiling, radiological techniques/reporting, targeted localized therapy, intricacies of systemic treatments, emerging tests, multidisciplinary care and patient advocacy. This literature review, along with clinical expertise and opinion, was used to develop this concise and clinically relevant consensus paper to harmonize the knowledge and clinical practice on GIST management across Canada. The content presented here will help guide healthcare providers, especially in Canada, in terms of approaching and managing GIST.
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Affiliation(s)
- J. Robert Beecroft
- Division of Interventional Radiology, Joint Department of Medical Imaging, University Health Network, Mount Sinai Hospital, Toronto, ON, Canada
| | - Savtaj Brar
- Department of Surgery, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
| | - Xiaolan Feng
- Division of Medical Oncology, Tom Baker Cancer Center, Calgary, AB, Canada
| | - Trevor Hamilton
- Department of Surgery, BC Cancer, Vancouver General Hospital, University of British Columbia, Vancouver, BC, Canada
| | - Cheng Han-Lee
- Department of Laboratory Medicine & Pathology, University of Alberta, Edmonton, AB, Canada
| | - Jan-Willem Henning
- Department of Oncology, Tom Baker Cancer Centre, Cuming School of Medicine, University of Calgary, Calgary, AB, Canada
| | | | - Korosh Khalili
- Department of Medical Imaging, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Yoo-Joung Ko
- Department of Medicine, St. Michael’s Hospital, Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Christopher Lemieux
- Division of Hematology and Medical Oncology, Centre Hospitalier Universitaire de Québec, Université Laval, Quebec City, QC, Canada
| | - David M. Liu
- Department of Radiology, University of British Columbia, School of Biomedical Engineering, Vancouver, BC, Canada
- Department of Interventional Radiology, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - D. Blair MacDonald
- Department of Medical Radiology, The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada
| | - Jonathan Noujaim
- Division of Medical Oncology, Hôpital Maisonneuve-Rosemont, University of Montreal, Montreal, QC, Canada
| | - Aaron Pollett
- Pathology and Laboratory Medicine, Division of Diagnostic Medical Genetics, Mount Sinai Hospital, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Abdulazeez Salawu
- Division of Medical Oncology, Princess Margaret Cancer Centre, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
| | - Ramy Saleh
- Division of Medical Oncology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Alannah Smrke
- Division of Medical Oncology, BC Cancer, University of British Columbia, Vancouver, BC, Canada
| | - Blair E. Warren
- Department of Medical Imaging, University of Toronto, Toronto, ON, Canada
| | - Kevin Zbuk
- Department of Oncology, McMaster University, Hamilton, ON, Canada
| | - Albiruni Abdul Razak
- Division of Medical Oncology, Princess Margaret Cancer Centre, Mount Sinai Hospital, University of Toronto, 610 University Ave., Toronto, ON M2G 2M9, Canada
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14
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Hoog CJPO', Mehra N, Maliepaard M, Bol K, Gelderblom H, Sonke GS, de Langen AJ, van de Donk NWCJ, Janssen JJWM, Minnema MC, van Erp NP, Boerrigter E. Dose selection of novel anticancer drugs: exposing the gap between selected and required doses. Lancet Oncol 2024; 25:e340-e351. [PMID: 39089312 DOI: 10.1016/s1470-2045(24)00134-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 02/23/2024] [Accepted: 02/27/2024] [Indexed: 08/03/2024]
Abstract
Historically, dose selection of anticancer drugs has mainly been based on establishing the maximum tolerated dose in phase 1 clinical trials with a traditional 3 plus 3 design. In the era of targeted therapies and immune-modulating agents, this approach does not necessarily lead to selection of the most favourable dose. This strategy can introduce potentially avoidable toxicity or inconvenience for patients. Multiple changes in drug development could lead to more rational dose selection, such as use of better predictive preclinical models, adaptive and randomised trial design, evaluation of multiple dose levels in late-phase development, assessment of target activity and saturation, and early biomarker use for efficacy and safety evaluation. In this Review, we evaluate the rationale and validation of dose selection in each phase of drug development for anticancer drugs approved by the European Medicines Agency and US Food and Drug Administration from Jan 1, 2020, to June 30, 2023, and give recommendations for dose optimisation to improve safety and patient convenience. In our evaluation, we classified 20 (65%) of the 31 recently registered anticancer agents as potential candidates for dose optimisation, which could be achieved either by reducing the dose (n=10 [32%]) or adjusting the dosage regimen (n=10 [32%]). Dose selection seemed to be adequately justified for nine (29%) of the drugs, whereas the reviewed data were inconclusive for formulating a recommendation on dose optimisation for two (6%) of the drugs.
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Affiliation(s)
| | - Niven Mehra
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Marc Maliepaard
- Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, Netherlands; Dutch Medicines Evaluation Board (CBG-MEB), Utrecht, Netherlands
| | - Kalijn Bol
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Hans Gelderblom
- Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands
| | - Gabe S Sonke
- Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Adrianus J de Langen
- Department of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Niels W C J van de Donk
- Department of Hematology, Amsterdam University Medical Center, location Vrije Universiteit Amsterdam, Cancer Center Amsterdam, Amsterdam, Netherlands
| | - Jeroen J W M Janssen
- Department of Hematology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Monique C Minnema
- Department of Hematology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Nielka P van Erp
- Department of Pharmacy, Radboud University Medical Center, Nijmegen, Netherlands.
| | - Emmy Boerrigter
- Department of Pharmacy, Radboud University Medical Center, Nijmegen, Netherlands
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15
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Tsai HJ, Shan YS, Yang CY, Hsiao CF, Tsai CH, Wang CC, Lin MT, Ting CF, Chan DC, Chen TH, Yen CC, Chen YY, Lin HY, Yeh TS, Ho CL, Shieh TY, Bai LY, Hsu JT, Chen IS, Chen LT, Yeh CN. Survival of advanced/recurrent gastrointestinal stromal tumors treated with tyrosine kinase inhibitors in Taiwan: a nationwide registry study. BMC Cancer 2024; 24:828. [PMID: 38992597 PMCID: PMC11238460 DOI: 10.1186/s12885-024-12567-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 06/26/2024] [Indexed: 07/13/2024] Open
Abstract
BACKGROUND Most gastrointestinal stromal tumors (GISTs) harbor c-KIT or PDGFRA mutations. Administration of tyrosine kinase inhibitors (TKIs) has significantly improved the survival of patients with GISTs. We aimed to evaluate the clinical outcome of advanced or recurrent GIST patients in Taiwan. METHODS Patients diagnosed between 2010 and 2020 were enrolled. The collected data included baseline characteristics, treatment pattern, treatment outcome, genetic aberrations and survival status. Progression-free survival (PFS) and overall survival (OS) were analyzed and plotted with the Kaplan-Meier method. Cox regression analysis was used to analyze the prognostic factors of survival. RESULTS A total of 224 patients with advanced or recurrent GISTs treated with TKIs were enrolled. All patients received imatinib treatment. Ninety-three and 42 patients received sunitinib and regorafenib treatment, respectively. The 48-month PFS and OS rates for patients treated with imatinib were 50.5% and 79.5%, respectively. c-KIT exon 9 and PDGFRA mutations were prognostic factors for a poor PFS and PDGFRA mutation was a prognostic factor for a poor OS in patients treated with imatinib in multivariate Cox regression analysis. The median PFS of patients who received sunitinib treatment was 12.76 months (95% confidence interval (CI), 11.01-14.52). Patients with c-KIT exon 9 mutations had a longer PFS than those with other genetic aberrations. The median PFS of patients treated with regorafenib was 7.14 months (95% CI, 3.39-10.89). CONCLUSIONS We present real-world clinical outcomes for advanced GIST patients treated with TKIs and identify mutational status as an independent prognostic factor for patient survival.
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Affiliation(s)
- Hui-Jen Tsai
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Yan-Shen Shan
- Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Ching-Yao Yang
- Department of Surgery, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chin-Fu Hsiao
- Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan
| | - Chung-Hsin Tsai
- Department of Surgery, MacKay Memorial Hospital and Mackay Medical College, Taipei, Taiwan
| | - Chuan-Cheng Wang
- Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan
| | - Ming-Tsan Lin
- Department of Surgery, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Chun-Fu Ting
- Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - De-Chuan Chan
- Division of General Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Te-Hung Chen
- Department of Surgery, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Chueh-Chuan Yen
- Division of Medical Oncology, Center for Immuno-Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
- Division of Clinical Research, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
- School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
- Institute of Biopharmaceutical Sciences, College of Pharmaceutical Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Yen-Yang Chen
- Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Hsuan-Yu Lin
- Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan
| | - Ta-Sen Yeh
- Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital, Linkou, Chang Gung University, Taoyuan, Taiwan
| | - Ching-Liang Ho
- Division of Hematology and Oncology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
- Division of Hematology and Oncology, Medical Department, Taipei Tzu Chi Hospital, Taipei, Taiwan
| | - Tze-Yu Shieh
- Division of Gastroenterology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan
| | - Li-Yaun Bai
- Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Jun-Te Hsu
- Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital, Linkou, Chang Gung University, Taoyuan, Taiwan
| | - I-Shu Chen
- Division of General Surgery, Department of Surgery, Kaohsiung Veterans General Hospital and National Yang Ming Chiao Tung University, Kaohsiung, Taiwan
| | - Li-Tzong Chen
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
- Department of Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
- Center for Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
| | - Chun-Nan Yeh
- Division of General Surgery, Department of Surgery, Chang Gung Memorial Hospital, Linkou, Chang Gung University, Taoyuan, Taiwan.
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan.
- School of Medicine, National Tsing Hua University, Hsinchu, Taiwan.
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16
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Mosele MF, Westphalen CB, Stenzinger A, Barlesi F, Bayle A, Bièche I, Bonastre J, Castro E, Dienstmann R, Krämer A, Czarnecka AM, Meric-Bernstam F, Michiels S, Miller R, Normanno N, Reis-Filho J, Remon J, Robson M, Rouleau E, Scarpa A, Serrano C, Mateo J, André F. Recommendations for the use of next-generation sequencing (NGS) for patients with advanced cancer in 2024: a report from the ESMO Precision Medicine Working Group. Ann Oncol 2024; 35:588-606. [PMID: 38834388 DOI: 10.1016/j.annonc.2024.04.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Revised: 04/17/2024] [Accepted: 04/18/2024] [Indexed: 06/06/2024] Open
Abstract
BACKGROUND Advancements in the field of precision medicine have prompted the European Society for Medical Oncology (ESMO) Precision Medicine Working Group to update the recommendations for the use of tumour next-generation sequencing (NGS) for patients with advanced cancers in routine practice. METHODS The group discussed the clinical impact of tumour NGS in guiding treatment decision using the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) considering cost-effectiveness and accessibility. RESULTS As for 2020 recommendations, ESMO recommends running tumour NGS in advanced non-squamous non-small-cell lung cancer, prostate cancer, colorectal cancer, cholangiocarcinoma, and ovarian cancer. Moreover, it is recommended to carry out tumour NGS in clinical research centres and under specific circumstances discussed with patients. In this updated report, the consensus within the group has led to an expansion of the recommendations to encompass patients with advanced breast cancer and rare tumours such as gastrointestinal stromal tumours, sarcoma, thyroid cancer, and cancer of unknown primary. Finally, ESMO recommends carrying out tumour NGS to detect tumour-agnostic alterations in patients with metastatic cancers where access to matched therapies is available. CONCLUSION Tumour NGS is increasingly expanding its scope and application within oncology with the aim of enhancing the efficacy of precision medicine for patients with cancer.
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Affiliation(s)
- M F Mosele
- INSERM U981, Gustave Roussy, Villejuif; Department of Cancer Medicine, Gustave Roussy, Villejuif, France
| | - C B Westphalen
- Comprehensive Cancer Center Munich & Department of Medicine III, University Hospital, LMU Munich, Munich
| | - A Stenzinger
- Institute of Pathology, University Hospital Heidelberg and Center for Personalized Medicine (ZPM), Heidelberg, Germany
| | - F Barlesi
- INSERM U981, Gustave Roussy, Villejuif; Department of Cancer Medicine, Gustave Roussy, Villejuif, France; Faculty of Medicine, Université Paris-Saclay, Kremlin Bicêtre
| | - A Bayle
- Faculty of Medicine, Université Paris-Saclay, Kremlin Bicêtre; Drug Development Department (DITEP), Gustave Roussy, Villejuif; Oncostat U1018, Inserm, Université Paris-Saclay, labeled Ligue Contre le Cancer, Villejuif; Service de Biostatistique et Epidémiologie, Gustave Roussy, Villejuif
| | - I Bièche
- Department of Genetics, Institut Curie, INSERM U1016, Université Paris Cité, Paris, France
| | - J Bonastre
- Oncostat U1018, Inserm, Université Paris-Saclay, labeled Ligue Contre le Cancer, Villejuif; Service de Biostatistique et Epidémiologie, Gustave Roussy, Villejuif
| | - E Castro
- Department of Medical Oncology, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre, Madrid
| | - R Dienstmann
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona; University of Vic-Central University of Catalonia, Vic, Spain; Oncoclínicas, São Paulo, Brazil
| | - A Krämer
- Clinical Cooperation Unit Molecular Hematology/Oncology, German Cancer Research Center (DKFZ), Heidelberg; Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany
| | - A M Czarnecka
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw; Department of Experimental Pharmacology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
| | - F Meric-Bernstam
- Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, USA
| | - S Michiels
- Oncostat U1018, Inserm, Université Paris-Saclay, labeled Ligue Contre le Cancer, Villejuif; Service de Biostatistique et Epidémiologie, Gustave Roussy, Villejuif
| | - R Miller
- Department of Medical Oncology, University College London, London; Department of Medical Oncology, St Bartholomew's Hospital, London, UK
| | - N Normanno
- Scientific Directorate, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
| | - J Reis-Filho
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York
| | - J Remon
- Department of Cancer Medicine, Gustave Roussy, Villejuif, France
| | - M Robson
- Breast Medicine and Clinical Genetics Services, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA
| | - E Rouleau
- Tumor Genetics Service, Medical Biology and Pathology Department, Gustave Roussy, Villejuif, France
| | - A Scarpa
- Section of Pathology, Department of Diagnostics and Public Health, University of Verona-School of Medicine, Verona, Italy
| | - C Serrano
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona
| | - J Mateo
- Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona
| | - F André
- INSERM U981, Gustave Roussy, Villejuif; Department of Cancer Medicine, Gustave Roussy, Villejuif, France; Faculty of Medicine, Université Paris-Saclay, Kremlin Bicêtre.
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17
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Chai Y, Lin B, Zhong J, Wu X, Lin X, Ge X, Jiang J, Liang Z, Liu S, Gu C. Long-term outcomes of endoscopic therapy versus surgical resection for 2-5 cm gastric gastrointestinal stromal tumors: A population-based comparative study. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2024; 50:108262. [PMID: 38531231 DOI: 10.1016/j.ejso.2024.108262] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 03/02/2024] [Accepted: 03/08/2024] [Indexed: 03/28/2024]
Abstract
BACKGROUND Endoscopic therapy (ET) of gastrointestinal stromal tumors (GIST) has become a viable treatment. We intended to compare long-term outcomes of ET versus surgical resection for 2-5 cm GIST using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS A multicenter retrospective study was conducted to compare the long-term outcomes of patients treated with ET and surgical resection for GIST. The multivariate Cox proportional hazards models were used to identify predictors for patients survival. To balance the clinicopathologic characteristics, a 1:1 propensity score matching (PSM) was utilized. RESULTS A total of 749 patients with 2-5 cm GIST were enrolled, of whom 113 accepted ET and 636 underwent surgical resection. Before PSM, there was no significant difference in long-term outcomes between ET and surgical resection (5-year overall survival (OS): 93.5% vs. 91.6%, P=0.374; 5-year cancer-specific survival (CSS): 99.1% vs. 96.5%, P=0.546; 10-year OS: 71.1% vs. 78.2%, P=0.374; 10-year CSS: 93.6% vs. 92.7%, P=0.546). After adjusting for the relevant variables using the multivariable Cox proportional hazards models, we observed that the ET and surgical resection groups were similar in OS (HR 0.726, 95%CI 0.457-1.153, P=0.175) and CSS (HR 1.286, 95%CI 0.474-3.488, P=0.621). After PSM, the long-term OS and CSS of patients with 2-5 cm GIST after ET and surgical resection were comparable. CONCLUSIONS We found that the long-term survival of patients with 2-5 cm gastric GIST after ET and surgical resection were comparable. Further high-quality studies are needed to confirm the role of ET in 2-5 cm GIST.
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Affiliation(s)
- Yixia Chai
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Bitao Lin
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Jun Zhong
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Xiaosheng Wu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Xin Lin
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Xiaoyue Ge
- Department of General Practice, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Jiayi Jiang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Zhenye Liang
- Department of Gastrointestinal Surgery, The Third Affiliated Hospital of Sun Yat-Sen University · Zhao Qing Hospital, Zhaoqing 526000, China.
| | - Side Liu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
| | - Chuncai Gu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
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18
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Li P, Xiao Y, Zhou L, Zhang X, Xu Y, Wang X, Zou M, Guo X. A bibliometric analysis of interstitial cells of Cajal research. Front Med (Lausanne) 2024; 11:1391545. [PMID: 38831987 PMCID: PMC11145981 DOI: 10.3389/fmed.2024.1391545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 03/25/2024] [Indexed: 06/05/2024] Open
Abstract
Objective The significance of interstitial cells of Cajal (ICC) in the gastrointestinal tract has garnered increasing attention. In recent years, approximately 80 articles on ICC have been published annually in various journals. However, no bibliometric study has specifically focused on the literature related to ICC. Therefore, we conducted a comprehensive bibliometric analysis of ICC to reveal dynamic scientific developments, assisting researchers in exploring hotspots and emerging trends while gaining a global perspective. Methods We conducted a literature search in the Web of Science Core Collection (WoSCC) from January 1, 2013, to December 31, 2023, to identify relevant literature on ICC. We employed bibliometric software, namely VOSviewer and CiteSpace, to analyze various aspects including annual publication output, collaborations, research hotspots, current status, and development trends in this domain. Results A total of 891 English papers were published in 359 journals by 928 institutions from 57 countries/regions. According to the keyword analysis of the literature, researchers mainly focused on "c-Kit," "expression," "smooth muscle," and "nitric oxide" related to ICC over the past 11 years. However, with "SIP syncytium," "ANO1," "enteric neurons," "gastrointestinal stromal tumors (GIST)," and "functional dyspepsia (FD)," there has been a growing interest in the relationship between ANO1, SIP syncytium, and ICC, as well as the role of ICC in the treatment of GIST and FD. Conclusion Bibliometric analysis has revealed the current status of ICC research. The association between ANO1, SIP syncytium, enteric neurons and ICC, as well as the role of ICC in the treatment of GIST versus FD has become the focus of current research. However, further research and collaboration on a global scale are still needed. Our analysis is particularly valuable to researchers in gastroenterology, oncology, and cell biology, providing insights that can guide future research directions.
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Affiliation(s)
- Pengyu Li
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Yadan Xiao
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Lan Zhou
- Integrated Traditional Chinese and Western Medicine Department, The Third Hospital of Changsha, Changsha, China
| | - Xuyuan Zhang
- School of Integrated Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, China
| | - Yin Xu
- Department of Gastroenterology, The First Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Xiaojuan Wang
- Department of Gastroenterology, The First Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Menglong Zou
- Department of Gastroenterology, The First Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Xuan Guo
- Science & Technology Innovation Center (National Key Laboratory Cultivation Base of Chinese Medicinal Powder & Innovative Medicinal Jointly Established by Province and Ministry), Hunan University of Chinese Medicine, Changsha, China
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19
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Mühlenberg T, Falkenhorst J, Schulz T, Fletcher BS, Teuber A, Krzeciesa D, Klooster I, Lundberg M, Wilson L, Lategahn J, von Mehren M, Grunewald S, Tüns AI, Wardelmann E, Sicklick JK, Brahmi M, Serrano C, Schildhaus HU, Sievers S, Treckmann J, Heinrich MC, Raut CP, Ou WB, Marino-Enriquez A, George S, Rauh D, Fletcher JA, Bauer S. KIT ATP-Binding Pocket/Activation Loop Mutations in GI Stromal Tumor: Emerging Mechanisms of Kinase Inhibitor Escape. J Clin Oncol 2024; 42:1439-1449. [PMID: 38408285 PMCID: PMC11095889 DOI: 10.1200/jco.23.01197] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 10/10/2023] [Accepted: 12/04/2023] [Indexed: 02/28/2024] Open
Abstract
PURPOSE Imatinib resistance in GI stromal tumors (GISTs) is primarily caused by secondary KIT mutations, and clonal heterogeneity of these secondary mutations represents a major treatment obstacle. KIT inhibitors used after imatinib have clinical activity, albeit with limited benefit. Ripretinib is a potent inhibitor of secondary KIT mutations in the activation loop (AL). However, clinical benefit in fourth line remains limited and the molecular mechanisms of ripretinib resistance are largely unknown. PATIENTS AND METHODS Progressing lesions of 25 patients with GISTs refractory to ripretinib were sequenced for KIT resistance mutations. Resistant genotypes were validated and characterized using novel cell line models and in silico modeling. RESULTS GISTs progressing on ripretinib were enriched for secondary mutations in the ATP-binding pocket (AP), which frequently occur in cis with preexisting AL mutations, resulting in highly resistant AP/AL genotypes. AP/AL mutations were rarely observed in a cohort of progressing GIST samples from the preripretinib era but represented 50% of secondary KIT mutations in patients with tumors resistant to ripretinib. In GIST cell lines harboring secondary KIT AL mutations, the sole genomic escape mechanisms during ripretinib drug selection were AP/AL mutations. Ripretinib and sunitinib synergize against mixed clones with secondary AP or AL mutants but do not suppress clones with AP/AL genotypes. CONCLUSION Our findings underscore that KIT remains the central oncogenic driver even in late lines of GIST therapy. KIT-inhibitor combinations may suppress resistance because of secondary KIT mutations. However, the emergence of KIT AP/AL mutations after ripretinib treatment calls for new strategies in the development of next-generation KIT inhibitors.
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Affiliation(s)
- Thomas Mühlenberg
- Department of Medical Oncology and Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany
- DKTK partner site Essen, German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Johanna Falkenhorst
- Department of Medical Oncology and Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany
- DKTK partner site Essen, German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Tom Schulz
- Department of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany
- Drug Discovery Hub Dortmund (DDHD) am Zentrum für Integrierte Wirkstoffforschung (ZIW), Dortmund, Germany
| | - Benjamin S. Fletcher
- Department of Medical Oncology and Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany
- DKTK partner site Essen, German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Alina Teuber
- Department of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany
- Drug Discovery Hub Dortmund (DDHD) am Zentrum für Integrierte Wirkstoffforschung (ZIW), Dortmund, Germany
| | - Dawid Krzeciesa
- Department of Medical Oncology and Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany
- DKTK partner site Essen, German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Isabella Klooster
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Meijun Lundberg
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Lydia Wilson
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Jonas Lategahn
- Department of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany
- Drug Discovery Hub Dortmund (DDHD) am Zentrum für Integrierte Wirkstoffforschung (ZIW), Dortmund, Germany
| | - Margaret von Mehren
- Department of Hematology and Oncology, Fox Chase Cancer Center, Temple Health System, University, Philadelphia, PA
| | - Susanne Grunewald
- Department of Medical Oncology and Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany
- DKTK partner site Essen, German Cancer Consortium (DKTK), Heidelberg, Germany
| | - Alicia Isabell Tüns
- Laboratory of Molecular Oncology, Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany
| | - Eva Wardelmann
- Gerhard Domagk Institute of Pathology, University Hospital Münster, Münster, Germany
| | - Jason K. Sicklick
- Department of Surgery, Division of Surgical Oncology, University of California San Diego, San Diego, CA
- Department of Pharmacology, Moores Cancer Center, University of California San Diego, San Diego, CA
| | - Mehdi Brahmi
- Centre Leon Berard, Medical Oncology, Lyon, France
| | - César Serrano
- Sarcoma Translational Research Laboratory, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Hans-Ulrich Schildhaus
- University Hospital Essen, Institute of Pathology, Essen, Germany
- Current affiliation: Discovery Life Sciences Biomarker Services & Institute of Pathology Nodhessen, Kassel, Germany
| | - Sonja Sievers
- Compound Management and Screening Center, Max Planck Institute of Molecular Physiology, Dortmund, Germany
| | - Jürgen Treckmann
- University of Duisburg-Essen, Medical School, Department of Visceral and Transplantation Surgery, Essen, Germany
| | - Michael C. Heinrich
- Portland VA Health Care System and OHSU Knight Cancer Institute, Portland, OR
| | - Chandrajit P. Raut
- Department of Surgery, Brigham and Women's Hospital, Boston, MA
- Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston, MA
- Harvard Medical School, Boston, MA
| | - Wen-Bin Ou
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
- Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, China
| | - Adrian Marino-Enriquez
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Suzanne George
- Dana-Farber Cancer Institute, Medical Oncology, Boston, MA
| | - Daniel Rauh
- Department of Chemistry and Chemical Biology, TU Dortmund University, Dortmund, Germany
- Drug Discovery Hub Dortmund (DDHD) am Zentrum für Integrierte Wirkstoffforschung (ZIW), Dortmund, Germany
| | - Jonathan A. Fletcher
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA
| | - Sebastian Bauer
- Department of Medical Oncology and Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School, Essen, Germany
- DKTK partner site Essen, German Cancer Consortium (DKTK), Heidelberg, Germany
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20
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Fontebasso AM, Rytlewski JD, Blay JY, Gladdy RA, Wilky BA. Precision Oncology in Soft Tissue Sarcomas and Gastrointestinal Stromal Tumors. Surg Oncol Clin N Am 2024; 33:387-408. [PMID: 38401916 DOI: 10.1016/j.soc.2023.12.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/26/2024]
Abstract
Soft tissue sarcomas (STSs), including gastrointestinal stromal tumors (GISTs), are mesenchymal neoplasms with heterogeneous clinical behavior and represent broad categories comprising multiple distinct biologic entities. Multidisciplinary management of these rare tumors is critical. To date, multiple studies have outlined the importance of biological characterization of mesenchymal tumors and have identified key molecular alterations which drive tumor biology. GIST has represented a flagship for targeted therapy in solid tumors with the advent of imatinib which has revolutionized the way we treat this malignancy. Herein, the authors discuss the importance of biological and molecular diagnostics in managing STS and GIST patients.
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Affiliation(s)
- Adam M Fontebasso
- Division of Surgical Oncology, Department of Surgery, University of Toronto, 700 University Avenue, 7th Floor, Ontario Power Generation Building, Toronto, Ontario, Canada; Department of Surgery, Mount Sinai Hospital, Sinai Health Systems, 600 University Avenue Room 6-445.10 Surgery, Toronto, Ontario M5G 1X5, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Jeffrey D Rytlewski
- University of Colorado School of Medicine, 12801 East 17th Avenue, Mailstop 8117, Aurora, CO 80045, USA
| | - Jean-Yves Blay
- Centre Léon Bérard, 28, rue Laennec, 69373 cedex 08. Lyon, France
| | - Rebecca A Gladdy
- Division of Surgical Oncology, Department of Surgery, University of Toronto, 700 University Avenue, 7th Floor, Ontario Power Generation Building, Toronto, Ontario, Canada; Department of Surgery, Mount Sinai Hospital, Sinai Health Systems, 600 University Avenue Room 6-445.10 Surgery, Toronto, Ontario M5G 1X5, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
| | - Breelyn A Wilky
- University of Colorado School of Medicine, 12801 East 17th Avenue, Mailstop 8117, Aurora, CO 80045, USA.
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21
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de Villenfagne L, Sablon A, Demoulin JB. PDGFRA K385 mutants in myxoid glioneuronal tumors promote receptor dimerization and oncogenic signaling. Sci Rep 2024; 14:7204. [PMID: 38532028 DOI: 10.1038/s41598-024-57859-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 03/22/2024] [Indexed: 03/28/2024] Open
Abstract
Myxoid glioneuronal tumors (MGNT) are low-grade glioneuronal neoplasms composed of oligodendrocyte-like cells in a mucin-rich stroma. These tumors feature a unique dinucleotide change at codon 385 in the platelet-derived growth factor receptor α (encoded by the PDGFRA gene), resulting in the substitution of lysine 385 into leucine or isoleucine. The functional consequences of these mutations remain largely unexplored. Here, we demonstrated their oncogenic potential in fibroblast and Ba/F3 transformation assays. We showed that the K385I and K385L mutants activate STAT and AKT signaling in the absence of ligand. Co-immunoprecipitations and BRET experiments suggested that the mutations stabilized the active dimeric conformation of the receptor, pointing to a new mechanism of oncogenic PDGF receptor activation. Furthermore, we evaluated the sensitivity of these mutants to three FDA-approved tyrosine kinase inhibitors: imatinib, dasatinib, and avapritinib, which effectively suppressed the constitutive activity of the mutant receptors. Finally, K385 substitution into another hydrophobic amino acid also activated the receptor. Interestingly, K385M was reported in a few cases of brain tumors but not in MGNT. Our results provide valuable insights into the molecular mechanism underlying the activation of PDGFRα by the K385I/L mutations, highlighting their potential as actionable targets in the treatment of myxoid glioneuronal tumors.
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Affiliation(s)
- Laurence de Villenfagne
- De Duve Institute, University of Louvain, Avenue Hippocrate 75, Box B1.74.05, 1200, Brussels, Belgium
| | - Ariane Sablon
- De Duve Institute, University of Louvain, Avenue Hippocrate 75, Box B1.74.05, 1200, Brussels, Belgium
| | - Jean-Baptiste Demoulin
- De Duve Institute, University of Louvain, Avenue Hippocrate 75, Box B1.74.05, 1200, Brussels, Belgium.
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22
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Liu X, Yu J, Li Y, Shi H, Jiao X, Liu X, Guo D, Li Z, Tian Y, Dai F, Niu Z, Zhou Y. Deciphering the tumor immune microenvironment of imatinib-resistance in advanced gastrointestinal stromal tumors at single-cell resolution. Cell Death Dis 2024; 15:190. [PMID: 38443340 PMCID: PMC10914684 DOI: 10.1038/s41419-024-06571-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 02/16/2024] [Accepted: 02/21/2024] [Indexed: 03/07/2024]
Abstract
The heterogeneous nature of tumors presents a considerable obstacle in addressing imatinib resistance in advanced cases of gastrointestinal stromal tumors (GIST). To address this issue, we conducted single-cell RNA-sequencing in primary tumors as well as peritoneal and liver metastases from patients diagnosed with locally advanced or advanced GIST. Single-cell transcriptomic signatures of tumor microenvironment (TME) were analyzed. Immunohistochemistry and multiplex immunofluorescence staining were used to further validate it. This analysis revealed unique tumor evolutionary patterns, transcriptome features, dynamic cell-state changes, and different metabolic reprogramming. The findings indicate that in imatinib-resistant TME, tumor cells with activated immune and cytokine-mediated immune responses interacted with a higher proportion of Treg cells via the TIGIT-NECTIN2 axis. Future immunotherapeutic strategies targeting Treg may provide new directions for the treatment of imatinib-resistant patients. In addition, IDO1+ dendritic cells (DC) were highly enriched in imatinib-resistant TME, interacting with various myeloid cells via the BTLA-TNFRSF14 axis, while the interaction was not significant in imatinib-sensitive TME. Our study highlights the transcriptional heterogeneity and distinct immunosuppressive microenvironment of advanced GIST, which provides novel therapeutic strategies and innovative immunotherapeutic agents for imatinib resistance.
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Affiliation(s)
- Xuechao Liu
- Department of General Surgery, Affiliated Hospital of Qingdao University, 16# Jiangsu Road, Qingdao, Shandong, China
| | - Jing Yu
- School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China
| | - Yi Li
- Department of General Surgery, Affiliated Hospital of Qingdao University, 16# Jiangsu Road, Qingdao, Shandong, China
| | - Hailei Shi
- Pathology Department, Affiliated Hospital of Qingdao University, 16# Jiangsu Road, Qingdao, Shandong, China
| | - Xuelong Jiao
- Department of General Surgery, Affiliated Hospital of Qingdao University, 16# Jiangsu Road, Qingdao, Shandong, China
| | - Xiaodong Liu
- Department of General Surgery, Affiliated Hospital of Qingdao University, 16# Jiangsu Road, Qingdao, Shandong, China
| | - Dong Guo
- Department of General Surgery, Affiliated Hospital of Qingdao University, 16# Jiangsu Road, Qingdao, Shandong, China
| | - Zequn Li
- Department of General Surgery, Affiliated Hospital of Qingdao University, 16# Jiangsu Road, Qingdao, Shandong, China
| | - Yulong Tian
- Department of General Surgery, Affiliated Hospital of Qingdao University, 16# Jiangsu Road, Qingdao, Shandong, China
| | - Fan Dai
- Zhejiang Provincial Key Laboratory of Crop Genetic Resources, Institute of Crop Science, Plant Precision Breeding Academy, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, 310058, Zhejiang, China.
| | - Zhaojian Niu
- Department of General Surgery, Affiliated Hospital of Qingdao University, 16# Jiangsu Road, Qingdao, Shandong, China.
| | - Yanbing Zhou
- Department of General Surgery, Affiliated Hospital of Qingdao University, 16# Jiangsu Road, Qingdao, Shandong, China.
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Boucher R, Haigh O, Barreau E, Champiat S, Lambotte O, Adam C, Labetoulle M, Rousseau A. Ocular surface toxicities associated with modern anticancer therapies. Surv Ophthalmol 2024; 69:198-210. [PMID: 37806566 DOI: 10.1016/j.survophthal.2023.10.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 09/25/2023] [Accepted: 10/03/2023] [Indexed: 10/10/2023]
Abstract
Cancer treatments have recently shifted from broad-spectrum cytotoxic therapies to more focused treatments, maximizing anticancerous activity while reducing toxicity to healthy cells. These modern anticancer therapies (MATs) encompass a wide range of innovative molecules that include immune checkpoint inhibitors and other targeted anticancer therapies, comprising antibody drug conjugates and inhibitors of signal transduction. Some MATs are associated with ocular surface adverse events that can cause severe discomfort and even lead to loss of vision. While these complications remain rare, they are probably underreported. It is likely that both oncologists and ophthalmologists will come across MATs-associated ocular surface-adverse events in their practices, owing to the increasing number of patients being treated with MATs. Rapid identification of ocular surface-adverse events is crucial, as early intervention can manage these conditions to avoid vision loss and reduce negative impacts on quality of life. We discuss characteristics of ocular surface pathologies attributed to MATs, describe the suspected underlying pathophysiological mechanisms, and outline the main lines of treatment.
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Affiliation(s)
- Rafael Boucher
- Service d'Ophtalmologie, Assistance Publique Hôpitaux de Paris (AP-HP), Université Paris-Saclay. Centre de Référence pour les maladies rares en ophtalmologie (OPHTARA), Le Kremlin-Bicêtre, France; Department of Immunology of Viral and Auto-immune Disease (IMVA DSV/iMETI/IDMIT), UMR1184, CEA, Fontenay-aux-Roses, France
| | - Oscar Haigh
- Department of Immunology of Viral and Auto-immune Disease (IMVA DSV/iMETI/IDMIT), UMR1184, CEA, Fontenay-aux-Roses, France
| | - Emmanuel Barreau
- Service d'Ophtalmologie, Assistance Publique Hôpitaux de Paris (AP-HP), Université Paris-Saclay. Centre de Référence pour les maladies rares en ophtalmologie (OPHTARA), Le Kremlin-Bicêtre, France
| | - Stéphane Champiat
- Département d'Innovation Thérapeutique et d'Essais Précoces (DITEP), Gustave Roussy, Villejuif, France
| | - Olivier Lambotte
- Department of Immunology of Viral and Auto-immune Disease (IMVA DSV/iMETI/IDMIT), UMR1184, CEA, Fontenay-aux-Roses, France; Department of Internal Medicine and Immunology, Assistance Publique Hôpitaux de Paris (AP-HP), Université Paris-Saclay, Le Kremlin-Bicêtre, France
| | - Clovis Adam
- Department of Pathology, Assistance Publique Hôpitaux de Paris (AP-HP), Université Paris-Saclay, Le Kremlin-Bicêtre, France
| | - Marc Labetoulle
- Service d'Ophtalmologie, Assistance Publique Hôpitaux de Paris (AP-HP), Université Paris-Saclay. Centre de Référence pour les maladies rares en ophtalmologie (OPHTARA), Le Kremlin-Bicêtre, France; Department of Immunology of Viral and Auto-immune Disease (IMVA DSV/iMETI/IDMIT), UMR1184, CEA, Fontenay-aux-Roses, France
| | - Antoine Rousseau
- Service d'Ophtalmologie, Assistance Publique Hôpitaux de Paris (AP-HP), Université Paris-Saclay. Centre de Référence pour les maladies rares en ophtalmologie (OPHTARA), Le Kremlin-Bicêtre, France; Department of Immunology of Viral and Auto-immune Disease (IMVA DSV/iMETI/IDMIT), UMR1184, CEA, Fontenay-aux-Roses, France.
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24
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Cicala CM, Olivares-Rivas I, Aguirre-Carrillo JA, Serrano C. KIT/PDGFRA inhibitors for the treatment of gastrointestinal stromal tumors: getting to the gist of the problem. Expert Opin Investig Drugs 2024; 33:159-170. [PMID: 38344849 DOI: 10.1080/13543784.2024.2318317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Accepted: 02/09/2024] [Indexed: 02/15/2024]
Abstract
INTRODUCTION Approximately 90% of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in receptor tyrosine-kinases KIT or PDGFRA. Despite the outstanding results of first-line imatinib in advanced GIST, resistance ultimately occurs mainly through secondary mutations in KIT/PDGFRA. Other tyrosine-kinase inhibitors (TKIs) with a broader spectrum of activity against these mutations are approved after imatinib failure. However, response rates and progression-free survival are drastically lower compared to imatinib. Notably, imatinib also triggers early tolerance adaptation mechanisms, which precede the occurrence of secondary mutations. AREAS COVERED In this review, we outline the current landscape of KIT inhibitors, discuss the novel agents, and present additional biological pathways that may be therapeutically exploitable. EXPERT OPINION The development of broad-spectrum and highly selective TKIs able to induce a sustained KIT/PDGFRA inhibition is the pillar of preclinical and clinical investigation in GIST. However, it is now recognized that the situation is more intricate, with various factors interacting with KIT and PDGFRA, playing a crucial role in the response and resistance to treatments. Future strategies in the management of advanced GIST should integrate driver inhibition with the blockade of other molecules to enhance cell death and establish enduring responses in patients.
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Affiliation(s)
- Carlo María Cicala
- Sarcoma Translational Research Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Iván Olivares-Rivas
- Sarcoma Translational Research Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | | | - César Serrano
- Sarcoma Translational Research Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain
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25
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Heinrich MC, Zhang X, Jones RL, George S, Serrano C, Deng Y, Bauer S, Cai S, Wu X, Zhou Y, Tao K, Zheng Z, Zhang J, Cui Y, Cao H, Wang M, Hu J, Yang J, Li J, Shen L. Clinical Benefit of Avapritinib in KIT-Mutant Gastrointestinal Stromal Tumors: A Post Hoc Analysis of the Phase I NAVIGATOR and Phase I/II CS3007-001 Studies. Clin Cancer Res 2024; 30:719-728. [PMID: 38032349 DOI: 10.1158/1078-0432.ccr-23-1861] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 09/25/2023] [Accepted: 11/27/2023] [Indexed: 12/01/2023]
Abstract
PURPOSE The efficacy of the selective KIT/PDGFRA inhibitor avapritinib (300 mg once daily) was explored in patients with non-PDGFRA-mutant gastrointestinal stromal tumors (GISTs) from the phase I NAVIGATOR and phase I/II CS3007-001 trials. PATIENTS AND METHODS Adults with unresectable/metastatic, KIT-only-mutant GISTs and progression following ≥1 tyrosine kinase inhibitors (TKIs) were included in this post hoc analysis. Baseline mutational status was identified in tumor and plasma. Primary endpoints were objective response rate (ORR) and progression-free survival (PFS) by blinded independent radiology review per modified RECIST v1.1 in patients harboring KIT activation-loop mutations (KIT exons 17 or 18) without ATP binding-pocket mutations (KIT exons 13 or 14; ALposABPneg), and other KIT mutations (OTHERS). RESULTS Sixty KIT ALposABPneg and 100 KIT OTHERS predominantly heavily pretreated patients (61.3% with ≥3 prior TKIs) were included. ORR was significantly higher in KIT ALposABPneg than KIT OTHERS patients (unadjusted: 26.7% vs. 12.0%; P = 0.0852; adjusted: 31.4% vs. 12.1%; P = 0.0047). Median PFS (mPFS) was significantly longer in KIT ALposABPneg patients compared with KIT OTHERS patients (unadjusted: 9.1 vs. 3.5 months; P = 0.0002; adjusted: 9.1 vs. 3.4 months; P < 0.0001), and longer in second- versus later-line settings (19.3 vs. 5.6-10.6 months). Benefit with avapritinib was observed in patients with KIT exon 9 mutations in the ≥4 line settings (mPFS: 5.6 and 3.7 months for 4 line and >4 line, respectively). CONCLUSIONS Avapritinib showed greater antitumor activity in patients with GISTs harboring KIT ALposABPneg mutations versus KIT OTHERS, and may be considered in the former subpopulation. Patients with KIT exon 9 mutations may also benefit in ≥4 line settings.
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Affiliation(s)
- Michael C Heinrich
- Portland VA Health Care System and OHSU Knight Cancer Institute, Portland, Oregon
| | - Xinhua Zhang
- Center for Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Robin L Jones
- Royal Marsden Hospital and Institute of Cancer Research, Chelsea, London, United Kingdom
| | - Suzanne George
- Sarcoma Center, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - César Serrano
- Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Yanhong Deng
- Department of Medical Oncology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Sebastian Bauer
- Department of Medical Oncology, West German Cancer Center, Essen, Germany
| | - Shirong Cai
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xin Wu
- Department of General Surgery, Chinese PLA General Hospital, Beijing, China
| | - Yongjian Zhou
- Department of Gastroenterology, Fujian Medical University Union Hospital, Fuzhou, Fujian, China
| | - Kaixiong Tao
- Department of Gastroenterology, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhichao Zheng
- Department of Gastrosurgery, Liaoning Cancer Hospital & Institute, Shenyang, Liaoning, China
| | - Jun Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yuehong Cui
- Department of Medical Oncology, Fudan University Zhongshan Hospital, Shanghai, China
| | - Hui Cao
- Department of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Meining Wang
- Medical Affairs, CStone Pharmaceuticals (Suzhou), Suzhou, China
| | - Jin Hu
- Clinical Department, CStone Pharmaceuticals (Suzhou), Suzhou, China
| | - Jason Yang
- Clinical Department, CStone Pharmaceuticals (Suzhou), Suzhou, China
| | - Jian Li
- Department of Gastrointestinal Oncology, Laboratory of Carcinogenesis and Translational Research of the Ministry of Education, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, China
| | - Lin Shen
- Department of Gastrointestinal Oncology, Laboratory of Carcinogenesis and Translational Research of the Ministry of Education, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, China
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26
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Ding G, Yu H, Jin J, Qiao X, Ma J, Zhang T, Cheng X. Reciprocal relationship between cancer stem cells and myeloid-derived suppressor cells: implications for tumor progression and therapeutic strategies. Future Oncol 2024; 20:215-228. [PMID: 38390682 DOI: 10.2217/fon-2023-0907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/24/2024] Open
Abstract
Recently, there has been an increased focus on cancer stem cells (CSCs) due to their resilience, making them difficult to eradicate. This resilience often leads to tumor recurrence and metastasis. CSCs adeptly manipulate their surroundings to create an environment conducive to their survival. In this environment, myeloid-derived suppressor cells (MDSCs) play a crucial role in promoting epithelial-mesenchymal transition and bolstering CSCs' stemness. In response, CSCs attract MDSCs, enhancing their infiltration, expansion and immunosuppressive capabilities. This interaction between CSCs and MDSCs increases the difficulty of antitumor therapy. In this paper, we discuss the interplay between CSCs and MDSCs based on current research and highlight recent therapeutic strategies targeting either CSCs or MDSCs that show promise in achieving effective antitumor outcomes.
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Affiliation(s)
- Guiqing Ding
- Institute of Clinical Immunology, Yue-yang Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China
| | - Hua Yu
- Institute of Clinical Immunology, Yue-yang Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China
| | - Jason Jin
- Institute of Clinical Immunology, Yue-yang Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China
| | - Xi Qiao
- Institute of Clinical Immunology, Yue-yang Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China
| | - Jinyun Ma
- Institute of Clinical Immunology, Yue-yang Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China
| | - Tong Zhang
- Institute of Clinical Immunology, Yue-yang Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China
| | - Xiaodong Cheng
- Institute of Clinical Immunology, Yue-yang Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 200437, China
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27
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Huang C, Ma X, Wang M, Cao H. Drugs in the GIST Field (Therapeutic Targets and Clinical Trial Staging). Curr Drug Deliv 2024; 21:80-90. [PMID: 36415101 PMCID: PMC10661963 DOI: 10.2174/1567201820666221122120657] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 10/15/2022] [Accepted: 10/20/2022] [Indexed: 11/24/2022]
Abstract
BACKGROUND Molecular targeted therapies are the most important type of medical treatment for GIST, but the development of GIST drugs and their targets have not been summarized. METHODS Drugs in the field of GIST were analyzed and collated through Pharmaprojects, ClinicalTrials. gov and PharmaGO databases. RESULTS As of 2021, there are 75 drugs that have appeared in the GIST clinical trials. The six most frequent targets in GIST clinical trials, in descending order of frequency, were KIT, PDGFRA, KDR (VEGFR2), FLT3, FLT1 (VEGFR1), and FLT4/VEGFR3. Only 8 drugs are in preclinical research. There are challenges in the development of new drugs for GIST. CONCLUSION This article analyzes and summarizes the general situation of GIST drugs, the target distribution of GIST drugs, and the trends in GIST drug-related clinical trials.
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Affiliation(s)
- Chen Huang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Xinli Ma
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ming Wang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hui Cao
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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28
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Li C, Wang Q, Jiang KW, Ye YJ. Hallmarks and novel insights for gastrointestinal stromal tumors: A bibliometric analysis. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2023; 49:107079. [PMID: 37826966 DOI: 10.1016/j.ejso.2023.107079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Accepted: 09/13/2023] [Indexed: 10/14/2023]
Abstract
BACKGROUND Due to the increasing recognition of gastrointestinal stromal tumor (GIST), novel insights have appeared in both preclinical and clinical research and begun to reshape the field. This study aims to map the research landscape through bibliometric analysis and provide a brief overview for the future of the GIST field. METHODS We searched the Web of Science Core Collection without publication data restrictions for GISTs and performed a bibliometric analysis with CiteSpace and VOSviewer software. RESULTS In sum, 5,911 of 13,776 records were included, and these studies were published in 948 journals and written by 24,965 authors from 4,633 institutions in 100 countries. Referring to published reviews and bibliometric analysis, we classified the future trends in four groups. In epidemiological study, precise incidence and clinicopathological features in different regions and races might become potential hotspots. Novel therapy, such as drugs, modified strategies, radioligand therapy, was persistent hotspots in GIST fields, and ctDNA-guided diagnosis, monitoring, and treatment might meet future clinical needs. The debate over serosa surgery vs. mucosa surgery will remain active for a long time in GIST surgery, and function reserve surgery, biology-based surgery will play an important role in future. Moreover, rare GIST type, like NF-1-associated GIST, Carney triads and SDH mutant GIST, need more studies in pathogenesis and genetic mutation to provide appropriate treatment for this orphan GIST patients. CONCLUSIONS Potential hotspots in future GIST trends might involve epidemiology, agents, resection therapy and rare type GIST, moreover, researchers could pay more attention in these four fields.
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Affiliation(s)
- Chen Li
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing, 100044, China
| | - Quan Wang
- Ambulatory Surgery Center, Xijing Hospital, Air Force Military Medical University, Xi'an, 710032, China
| | - Ke-Wei Jiang
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing, 100044, China.
| | - Ying-Jiang Ye
- Department of Gastroenterological Surgery, Laboratory of Surgical Oncology, Beijing Key Laboratory of Colorectal Cancer Diagnosis and Treatment Research, Peking University People's Hospital, Beijing, 100044, China.
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29
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Jones RL, Golčić M. Recent advances in the systemic treatment of gastrointestinal stromal tumors. Cancer Biol Med 2023; 20:j.issn.2095-3941.2023.0302. [PMID: 37874125 PMCID: PMC10618945 DOI: 10.20892/j.issn.2095-3941.2023.0302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 09/15/2023] [Indexed: 10/25/2023] Open
Affiliation(s)
- Robin L Jones
- Sarcoma Unit, The Royal Marsden NHS Foundation Trust and Institute of Cancer Research, Fulham Road, London SW3 6JJ, United Kingdom
| | - Marin Golčić
- Clinic for Tumors, Clinical Hospital Center, Rijeka 51000, Croatia
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30
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Serrano C, Martín-Broto J, Asencio-Pascual JM, López-Guerrero JA, Rubió-Casadevall J, Bagué S, García-del-Muro X, Fernández-Hernández JÁ, Herrero L, López-Pousa A, Poveda A, Martínez-Marín V. 2023 GEIS Guidelines for gastrointestinal stromal tumors. Ther Adv Med Oncol 2023; 15:17588359231192388. [PMID: 37655207 PMCID: PMC10467260 DOI: 10.1177/17588359231192388] [Citation(s) in RCA: 47] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 07/19/2023] [Indexed: 09/02/2023] Open
Abstract
Gastrointestinal stromal tumor (GIST) is the most common malignant neoplasm of mesenchymal origin. GIST spans a wide clinical spectrum that ranges from tumors with essentially no metastatic potential to malignant and life-threatening spread diseases. Gain-of-function mutations in KIT or PDGFRA receptor tyrosine kinases are the crucial drivers of most GISTs, responsible for tumor initiation and evolution throughout the entire course of the disease. The introduction of tyrosine kinase inhibitors targeting these receptors has substantially improved the outcomes in this formerly chemoresistant cancer. As of today, five agents hold regulatory approval for the treatment of GIST: imatinib, sunitinib, regorafenib, ripretinib, and avapritinib. This, in turn, represents a success for a rare neoplasm. During the past two decades, GIST has become a paradigmatic model in cancer for multidisciplinary work, given the disease-specific particularities regarding tumor biology and tumor evolution. Herein, we review currently available evidence for the management of GIST. This clinical practice guideline has been developed by a multidisciplinary expert panel (oncologist, pathologist, surgeon, molecular biologist, radiologist, and representative of patients' advocacy groups) from the Spanish Group for Sarcoma Research, and it is conceived to provide, from a critical perspective, the standard approach for diagnosis, treatment, and follow-up.
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Affiliation(s)
- César Serrano
- Sarcoma Translational Research Group, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, Vall d’Hebron Barcelona Hospital Campus, Carrer de Natzaret, 115-117, Barcelona 08035, Spain
| | - Javier Martín-Broto
- Medical Oncology Department, Fundación Jimenez Diaz University Hospital, Madrid, Spain
- University Hospital General de Villalba, Madrid, Spain Instituto de investigación Sanitaria Fundación Jimenez Diaz (IIS/FJD; UAM), Madrid, Spain
| | - José Manuel Asencio-Pascual
- Department of General Surgery, Gregorio Marañón University Hospital, Madrid, Spain
- Department of Surgery, Universidad Complutense de Madrid, Madrid, Spain
| | | | - Jordi Rubió-Casadevall
- Department of Medical Oncology, Catalan Institute of Oncology, Girona Biomedical Research Institute (IDIBGI), Girona, Spain
| | - Silvia Bagué
- Department of Pathology, Santa Creu i Sant Pau University Hospital, Barcelona, Spain
| | - Xavier García-del-Muro
- Department of Medical Oncology, Institut Català d’Oncologia, IDIBELL and University of Barcelona, Barcelona, Spain
| | | | - Luís Herrero
- GIST advocacy group – Colectivo GIST, Valladolid, Spain
| | - Antonio López-Pousa
- Department of Pathology, Santa Creu i Sant Pau University Hospital, Barcelona, Spain
| | - Andrés Poveda
- Initia Oncologia, Hospital Quironsalud, Valencia, Spain
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Golčić M, Jones RL, Huang P, Napolitano A. Evaluation of Systemic Treatment Options for Gastrointestinal Stromal Tumours. Cancers (Basel) 2023; 15:4081. [PMID: 37627109 PMCID: PMC10452236 DOI: 10.3390/cancers15164081] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 07/28/2023] [Accepted: 08/01/2023] [Indexed: 08/27/2023] Open
Abstract
Gastrointestinal stromal tumours (GIST) are the most common mesenchymal tumours of the gastrointestinal tract. Surgical treatment is recommended for the majority of localised GIST, while systemic treatment is the cornerstone of management for metastatic or unresectable disease. While a three-year regimen of imatinib is the standard of care in the adjuvant setting, there is no precise recommendation for the duration of neoadjuvant treatment, where imatinib is usually given between 4 and 12 months. Continuous treatment with imatinib at a dose of 400 mg once per day is recommended for most patients with unresectable or metastatic GIST in the first line. An exception is represented by patients with tumours harbouring the imatinib-insensitive PDGFRA D842V mutation who would be better treated with avapritinib. Targeted therapies are also recommended in the presence of NTRK rearrangements and BRAF mutations, although limited data are available. While an increase in the dose of imatinib to 800 mg is an option for the second line, sunitinib is usually considered the standard of care. Similar outcomes were reported for ripretinib in patients with tumours harbouring KIT exon 11 mutation, with significantly fewer side effects. Regorafenib and ripretinib are the standards of care in the third and fourth lines, respectively. The recent development of various systemic treatment options allows for a more personalised approach based on the molecular profile of the GIST, patient characteristics, and the profile of medications' adverse events. A multidisciplinary approach is paramount since combining systemic treatment with locoregional treatment options and supportive care is vital for long-term survival.
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Affiliation(s)
- Marin Golčić
- Department of Radiotherapy and Oncology, Clinical Hospital Center Rijeka, Krešimirova 42, 51000 Rijeka, Croatia
| | - Robin L. Jones
- Sarcoma Unit, The Royal Marsden NHS Foundation Trust, Fulham Road, London SW3 6JJ, UK
| | - Paul Huang
- Division of Molecular Pathology, The Institute of Cancer Research, Sutton SM2 5NG, UK;
| | - Andrea Napolitano
- Sarcoma Unit, The Royal Marsden NHS Foundation Trust, Fulham Road, London SW3 6JJ, UK
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Wang S, Wang Y, Luo J, Wang H, Zhao Y, Nie Y, Yang J. Development and validation of a prognostic nomogram for gastrointestinal stromal tumors in the postimatinib era: A study based on the SEER database and a Chinese cohort. Cancer Med 2023; 12:15970-15982. [PMID: 37329178 PMCID: PMC10469741 DOI: 10.1002/cam4.6240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 05/27/2023] [Accepted: 06/02/2023] [Indexed: 06/18/2023] Open
Abstract
BACKGROUND After the standardization, recording and follow-up of imatinib use that significantly prolongs survival of gastrointestinal stromal tumors (GISTs), a comprehensive reassessment of the prognosis of GISTs is necessary and more conductive to treatment options. METHODS A total of 2185 GISTs between 2013 and 2016 were obtained from the Surveillance, Epidemiology, and End Results database and comprised our training (n = 1456) and internal validation cohorts (n = 729). The risk factors extracted from univariate and multivariate analyses were used to establish a predictive nomogram. The model was evaluated and tested in the validation cohort internally and in 159 patients with GIST diagnosed between January 2015 and June 2017 in Xijing Hospital externally. RESULTS The median OS was 49 months (range, 0-83 months) in the training cohort and 51 months (0-83 months) in the validation cohort. The concordance index (C-index) of the nomogram was 0.777 (95% CI, 0.752-0.802) and 0.7787 (0.7785, bootstrap corrected) in training and internal validation cohorts, respectively, and 0.7613 (0.7579, bootstrap corrected) in the external validation cohort. Receiver operating characteristic curves and calibration curves for 1-, 3-, and 5-year overall survival (OS) showed a high degree of discrimination and calibration. The area under the curve showed that the new model performed better than the TNM staging system. In addition, the model could be dynamically visualized on a webpage. CONCLUSION We developed a comprehensive survival prediction model for assessing the 1-, 3- and 5-year OS of patients with GIST in the postimatinib era. This predictive model outperforms the traditional TNM staging system and sheds light on the improvement of the prognostic prediction and the selection of treatment strategies for GISTs.
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Affiliation(s)
- Shu Wang
- Department of Digestive SurgeryXi Jing Hospital, The Fourth Military Medical UniversityXi'anChina
| | - Yuhao Wang
- Department of Digestive SurgeryXi Jing Hospital, The Fourth Military Medical UniversityXi'anChina
| | - Jialin Luo
- Department of Digestive SurgeryXi Jing Hospital, The Fourth Military Medical UniversityXi'anChina
| | - Haoyuan Wang
- Department of Digestive SurgeryXi Jing Hospital, The Fourth Military Medical UniversityXi'anChina
| | - Yan Zhao
- Department of Digestive SurgeryXi Jing Hospital, The Fourth Military Medical UniversityXi'anChina
| | - Yongzhan Nie
- State Key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive DiseasesThe Fourth Military Medical UniversityXi'anChina
| | - Jianjun Yang
- Department of Digestive SurgeryXi Jing Hospital, The Fourth Military Medical UniversityXi'anChina
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Hou F, Yao Y, Wei Y, Wang Y, Cao Y, Liu X, Zheng L, Zhang Q, Jiao Y, Chen Y, Meng Y, Sun Y, Wu Y, Wang J, Wang J, Wu Z, Zhang K, Wei M, Yang G. Design and discovery of new selective and potent VEGF receptor 2 tyrosine kinase inhibitors. Bioorg Med Chem 2023; 91:117404. [PMID: 37429211 DOI: 10.1016/j.bmc.2023.117404] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 06/29/2023] [Accepted: 07/02/2023] [Indexed: 07/12/2023]
Abstract
A series of novel substituted 4-anilinoquinazolines and their related compounds were designed and prepared by 3D modeling as potential inhibitors of VEGFR-2. Evaluation of VEGFR inhibitory activities suggested that compound I10 was a more potent (IC50 = 0.11 nM) VEGFR-2 inhibitor than most of the listed drugs. Kinase panel assays demonstrated that compound I10 was the selective VEGFR-2 inhibitor. The prediction of 3D modeling unveiled a unique binding mode of this lead compound to VEGFR-2. Compound I10 exhibited remarkable anti-angiogenesis and anti-proliferation in HUVEC at low nanomolar concentrations. PK studies indicated that the lead compound possessed adequate oral bioavailability in various species. In vivo subcutaneous tumor model demonstrated that oral administration of I10 demonstrated potent efficacy in inhibiting tumor growth and angiogenesis. All these results suggested compound I10 is a potential drug candidate for cancer treatment.
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Affiliation(s)
- Fei Hou
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, PR China
| | - Yuhong Yao
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, PR China
| | - Yujiao Wei
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, PR China
| | - Yubo Wang
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, PR China
| | - Yangzi Cao
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, PR China
| | - Xinqiang Liu
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, PR China
| | - Liting Zheng
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, PR China
| | - Qingqing Zhang
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, PR China
| | - Yue Jiao
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, PR China
| | - Yukun Chen
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, PR China
| | - Yue Meng
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, PR China
| | - Yue Sun
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, PR China
| | - Yanjie Wu
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, PR China
| | - Jiefu Wang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, PR China.
| | - Junfeng Wang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, PR China.
| | - Zhou Wu
- China Resources Biopharmaceutical Co., Ltd., Beijing 100100, PR China.
| | - Kun Zhang
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, PR China.
| | - Mingming Wei
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, PR China.
| | - Guang Yang
- The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, PR China.
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Serrano C, Bauer S, Gómez-Peregrina D, Kang YK, Jones RL, Rutkowski P, Mir O, Heinrich MC, Tap WD, Newberry K, Grassian A, Shi H, Bialick S, Schöffski P, Pantaleo MA, von Mehren M, Trent JC, George S. Circulating tumor DNA analysis of the phase III VOYAGER trial: KIT mutational landscape and outcomes in patients with advanced gastrointestinal stromal tumor treated with avapritinib or regorafenib. Ann Oncol 2023; 34:615-625. [PMID: 37105265 PMCID: PMC10330293 DOI: 10.1016/j.annonc.2023.04.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 04/05/2023] [Accepted: 04/06/2023] [Indexed: 04/29/2023] Open
Abstract
BACKGROUND The current treatment paradigm of imatinib-resistant metastatic gastrointestinal stromal tumor (GIST) does not incorporate KIT/PDGFRA genotypes in therapeutic drug sequencing, except for PDGFRA exon 18-mutant GIST that is indicated for avapritinib treatment. Here, circulating tumor DNA (ctDNA) sequencing was used to analyze plasma samples prospectively collected in the phase III VOYAGER trial to understand how the KIT/PDGFRA mutational landscape contributes to tyrosine kinase inhibitor (TKI) resistance and to determine its clinical validity and utility. PATIENTS AND METHODS VOYAGER (N = 476) compared avapritinib with regorafenib in patients with KIT/PDGFRA-mutant GIST previously treated with imatinib and one or two additional TKIs (NCT03465722). KIT/PDGFRA ctDNA mutation profiling of plasma samples at baseline and end of treatment was assessed with 74-gene Guardant360® CDx. Molecular subgroups were determined and correlated with outcomes. RESULTS A total of 386/476 patients with KIT/PDGFRA-mutant tumors underwent baseline (pre-trial treatment) ctDNA analysis; 196 received avapritinib and 190 received regorafenib. KIT and PDGFRA mutations were detected in 75.1% and 5.4%, respectively. KIT resistance mutations were found in the activation loop (A-loop; 80.4%) and ATP-binding pocket (ATP-BP; 40.8%); 23.4% had both. An average of 2.6 KIT mutations were detected per patient; 17.2% showed 4-14 different KIT resistance mutations. Of all pathogenic KIT variants, 28.0% were novel, including alterations in exons/codons previously unreported. PDGFRA mutations showed similar patterns. ctDNA-detected KIT ATP-BP mutations negatively prognosticated avapritinib activity, with a median progression-free survival (mPFS) of 1.9 versus 5.6 months for regorafenib. mPFS for regorafenib did not vary regardless of the presence or absence of ATP-BP/A-loop mutants and was greater than mPFS with avapritinib in this population. Secondary KIT ATP-BP pocket mutation variants, particularly V654A, were enriched upon disease progression with avapritinib. CONCLUSIONS ctDNA sequencing efficiently detects KIT/PDGFRA mutations and prognosticates outcomes in patients with TKI-resistant GIST treated with avapritinib. ctDNA analysis can be used to monitor disease progression and provide more personalized treatment.
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Affiliation(s)
- C Serrano
- Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona; Sarcoma Translational Research Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
| | - S Bauer
- Department of Medical Oncology, Sarcoma Center, West German Cancer Center, DKTK-Partner-Site, University of Duisburg-Essen, Essen, Germany
| | - D Gómez-Peregrina
- Sarcoma Translational Research Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Y-K Kang
- Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - R L Jones
- Royal Marsden Hospital and Institute of Cancer Research, London, UK
| | - P Rutkowski
- Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - O Mir
- Institut Gustave Roussy, Villejuif, France
| | - M C Heinrich
- Portland VA Health Care System and OHSU Knight Cancer Institute, Portland
| | - W D Tap
- Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York
| | - K Newberry
- Blueprint Medicines Corporation, Cambridge
| | - A Grassian
- Blueprint Medicines Corporation, Cambridge
| | - H Shi
- Blueprint Medicines Corporation, Cambridge
| | - S Bialick
- Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, USA
| | - P Schöffski
- Department of General Medicine Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium
| | - M A Pantaleo
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - M von Mehren
- Department of Hematology Oncology, Fox Chase Cancer Center, Philadelphia
| | - J C Trent
- Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, USA
| | - S George
- Department of Medical Oncology, Sarcoma Center, Dana-Farber Cancer Institute, Boston, USA
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Venkataraman V, George S, Cote GM. Molecular Advances in the Treatment of Advanced Gastrointestinal Stromal Tumor. Oncologist 2023:oyad167. [PMID: 37315115 PMCID: PMC10400151 DOI: 10.1093/oncolo/oyad167] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 05/19/2023] [Indexed: 06/16/2023] Open
Abstract
Most gastrointestinal stromal tumors (GIST) are driven by activating mutations in Proto-oncogene c-KIT (KIT) or PDGFRA receptor tyrosine kinases (RTK). The emergence of effective therapies targeting these mutations has revolutionized the management of advanced GIST. However, following initiation of first-line imatinib, a tyrosine kinase inhibitor (TKI), nearly all patients will develop resistance within 2 years through the emergence of secondary resistance mutations in KIT, typically in the Adenosine Triphosphate (ATP)-binding site or activation loop of the kinase domain. Moreover, some patients have de novo resistance to imatinib, such as those with mutations in PDGFRA exon 18 or those without KIT or PDGFRA mutation. To target resistance, research efforts are primarily focused on developing next-generation inhibitors of KIT and/or PDGFRA, which can inhibit alternate receptor conformations or unique mutations, and compounds that impact complimentary pathogenic processes or epigenetic events. Here, we review the literature on the medical management of high-risk localized and advanced GIST and provide an update on clinical trial approaches to this disease.
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Affiliation(s)
- Vinayak Venkataraman
- Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA
- Mass General Hospital Cancer Center, Center for Sarcoma and Connective Tissue Oncology, Boston, MA, USA
| | - Suzanne George
- Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA
| | - Gregory M Cote
- Mass General Hospital Cancer Center, Center for Sarcoma and Connective Tissue Oncology, Boston, MA, USA
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36
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Liu ZL, Chen HH, Zheng LL, Sun LP, Shi L. Angiogenic signaling pathways and anti-angiogenic therapy for cancer. Signal Transduct Target Ther 2023; 8:198. [PMID: 37169756 PMCID: PMC10175505 DOI: 10.1038/s41392-023-01460-1] [Citation(s) in RCA: 436] [Impact Index Per Article: 218.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 03/20/2023] [Accepted: 04/20/2023] [Indexed: 05/13/2023] Open
Abstract
Angiogenesis, the formation of new blood vessels, is a complex and dynamic process regulated by various pro- and anti-angiogenic molecules, which plays a crucial role in tumor growth, invasion, and metastasis. With the advances in molecular and cellular biology, various biomolecules such as growth factors, chemokines, and adhesion factors involved in tumor angiogenesis has gradually been elucidated. Targeted therapeutic research based on these molecules has driven anti-angiogenic treatment to become a promising strategy in anti-tumor therapy. The most widely used anti-angiogenic agents include monoclonal antibodies and tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor (VEGF) pathway. However, the clinical benefit of this modality has still been limited due to several defects such as adverse events, acquired drug resistance, tumor recurrence, and lack of validated biomarkers, which impel further research on mechanisms of tumor angiogenesis, the development of multiple drugs and the combination therapy to figure out how to improve the therapeutic efficacy. Here, we broadly summarize various signaling pathways in tumor angiogenesis and discuss the development and current challenges of anti-angiogenic therapy. We also propose several new promising approaches to improve anti-angiogenic efficacy and provide a perspective for the development and research of anti-angiogenic therapy.
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Affiliation(s)
- Zhen-Ling Liu
- Department of Medicinal Chemistry, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 210009, Nanjing, China
| | - Huan-Huan Chen
- Department of Medicinal Chemistry, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 210009, Nanjing, China
| | - Li-Li Zheng
- Department of Medicinal Chemistry, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 210009, Nanjing, China
| | - Li-Ping Sun
- Department of Medicinal Chemistry, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 210009, Nanjing, China.
| | - Lei Shi
- Department of Medicinal Chemistry, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 210009, Nanjing, China.
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Naito Y, Nishida T, Doi T. Current status of and future prospects for the treatment of unresectable or metastatic gastrointestinal stromal tumours. Gastric Cancer 2023; 26:339-351. [PMID: 36913072 PMCID: PMC10115693 DOI: 10.1007/s10120-023-01381-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 03/02/2023] [Indexed: 03/14/2023]
Abstract
Gastrointestinal stromal tumours (GISTs) are soft-tissue sarcomas of the gastrointestinal tract. Surgery is the standard treatment for localised disease, but the risk of relapse and progression to more advanced disease is substantial. Following the discovery of the molecular mechanisms underlying GISTs, targeted therapies for advanced GIST were developed, with the first being the tyrosine kinase inhibitor (TKI) imatinib. Imatinib is recommended in international guidelines as first-line therapy to reduce the risk of GIST relapse in high-risk patients, and for locally advanced, inoperable and metastatic disease. Unfortunately, imatinib resistance frequently occurs and, therefore, second-line (sunitinib) and third-line (regorafenib) TKIs have been developed. Treatment options are limited for patients with GIST that has progressed despite these therapies. A number of other TKIs for advanced/metastatic GIST have been approved in some countries. Ripretinib is approved as fourth-line treatment of GIST and avapritinib is approved for GIST harbouring specific genetic mutations, while larotrectinib and entrectinib are approved for solid tumours (including GIST) with specific genetic mutations. In Japan, pimitespib, a heat shock protein 90 (HSP90) inhibitor, is now available as a fourth-line therapy for GIST. Clinical studies of pimitespib have indicated that it has good efficacy and tolerability, importantly not displaying the ocular toxicity of previously developed HSP90 inhibitors. Additional approaches for advanced GIST have been investigated, including alternative uses of currently available TKIs (such as combination therapy), novel TKIs, antibody-drug conjugates, and immunotherapies. Given the poor prognosis of advanced GIST, the development of new therapies remains an important goal.
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Affiliation(s)
- Yoichi Naito
- Department of General Internal Medicine, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
- Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan.
- Department of Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
| | - Toshirou Nishida
- Department of Surgery, Japan Community Health Care Organization Osaka Hospital, Osaka, Japan
- National Cancer Center Hospital, Tsukiji, Tokyo, Japan
| | - Toshihiko Doi
- Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan
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Mechahougui H, Michael M, Friedlaender A. Precision Oncology in Gastrointestinal Stromal Tumors. Curr Oncol 2023; 30:4648-4662. [PMID: 37232809 DOI: 10.3390/curroncol30050351] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 04/18/2023] [Accepted: 04/25/2023] [Indexed: 05/27/2023] Open
Abstract
GIST (gastrointestinal stromal tumors) represent 20% of sarcomatous tumors and 1-2% of primary gastrointestinal cancers. They have an excellent prognosis when localized and resectable, though their prognosis is poor in the metastatic setting, with limited options after the second line until recently. Four lines are now standard in KIT-mutated GIST and one in PDGFRA-mutated GIST. An exponential growth of new treatments is expected in this era of molecular diagnostic techniques and systematic sequencing. Currently, the main challenge remains the emergence of resistance linked to secondary mutations caused by selective pressure induced by TKIs. Repeating biopsies to tailor treatments might be a step in the right direction, and liquid biopsies at progression may offer a non-invasive alternative. New molecules with wider KIT inhibition are under investigation and could change the catalog and the sequence of existing treatments. Combination therapies may also be an approach to overcome current resistance mechanisms. Here, we review the current epidemiology and biology of GIST and discuss future management options, with an emphasis on genome-oriented therapies.
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Affiliation(s)
- Hiba Mechahougui
- Oncology Department, Geneva University Hospital, 1205 Geneva, Switzerland
| | | | - Alex Friedlaender
- Oncology Department, Geneva University Hospital, 1205 Geneva, Switzerland
- Clinique Générale Beaulieu, 1206 Geneva, Switzerland
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Mohammadi M, IJzerman NS, Hollander DD, Bleckman RF, Oosten AW, Desar IME, Reyners AKL, Steeghs N, Gelderblom H. Improved Efficacy of First-Line Imatinib in Advanced Gastrointestinal Stromal Tumors (GIST): The Dutch GIST Registry Data. Target Oncol 2023; 18:415-423. [PMID: 37079223 DOI: 10.1007/s11523-023-00960-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/19/2023] [Indexed: 04/21/2023]
Abstract
BACKGROUND Patients with unresectable and metastasized gastrointestinal stromal tumor (GIST) experienced a remarkable improvement of progression-free survival (PFS) and overall survival (OS) after the introduction of imatinib. Our hypothesis is that the outcomes of treatment with imatinib are even better nowadays compared with the registration trials that were performed two decades ago. To study this, we used real-life data from a contemporary registry. METHODS A multicenter, retrospective study was performed by exploring clinical data from a prospective real-life clinical database, the Dutch GIST Registry (DGR). Patients with advanced GIST treated with first-line imatinib were included and PFS (primary outcome) and OS (secondary outcome) were analyzed. Results of our study were compared with published results of the European Organisation for Research and Treatment of Cancer (EORTC) 62005 trial, which marked the first era of imatinib in the treatment of GIST. RESULTS Overall, 420 of the 435 patients treated with imatinib in the DGR had recorded response evaluation and were included in the analysis. During a median follow-up of 35.0 months (range 2.0-136.0), progression of GIST was eventually observed in 217 patients (51.2%). The DGR cohort showed a longer median PFS (33.0 months, 95% confidence interval [CI] 28.4-37.6) compared with the EORTC 62005 trial (an estimated PFS of 19.5 months). Additionally, the median OS of 68.0 months (95% CI 56.1-80.0) was longer than the exposed median OS (46.8 months) published in the long-term follow-up results of the EORTC 62005 trial (median follow-up duration 10.9 years). CONCLUSION This study provides an update on outcomes of imatinib in the treatment of advanced GIST patients and demonstrates improved clinical outcomes since the first randomized studies of imatinib 2 decades ago. Furthermore, these results represent outcomes in real-world clinical practice and can serve as a reference when evaluating effectiveness of imatinib in patients with advanced GIST.
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Affiliation(s)
- Mahmoud Mohammadi
- Department of Medical Oncology, Leiden University Medical Center, Leiden, 2300 RC, The Netherlands.
| | - Nikki S IJzerman
- Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Dide den Hollander
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Roos F Bleckman
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Astrid W Oosten
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Ingrid M E Desar
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - An K L Reyners
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Neeltje Steeghs
- Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Hans Gelderblom
- Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands
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Teranishi R, Takahashi T, Kurokawa Y, Saito T, Yamamoto K, Yamashita K, Tanaka K, Makino T, Nakajima K, Eguchi H, Doki Y. Long-term response to pimitespib in postoperative recurrent gastrointestinal stromal tumors with PDGFRA D842V mutation: a case report. Surg Case Rep 2023; 9:54. [PMID: 37027098 PMCID: PMC10082137 DOI: 10.1186/s40792-023-01637-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 04/01/2023] [Indexed: 04/08/2023] Open
Abstract
BACKGROUND Exon 18 D842V, which is a point mutation from aspartic acid to valine at codon 842, is the most frequent mutation in Platelet-Derived Growth Factor Receptor alpha (PDGFRA)-mutated gastrointestinal stromal tumor (GIST). In the Japanese GIST guidelines, no standard systematic therapy is available for this type of GIST, which is refractory after recurrence. Recently, pimitespib (PIMI), a novel heat shock protein 90 (HSP90) inhibitor, was approved for the treatment of advanced GIST in a phase III study. This report presents a case of a long-term response to PIMI in GIST with PDGFRA D842V mutation. CASE PRESENTATION A 55-year-old woman was diagnosed with primary GIST of the stomach and underwent partial gastrectomy. Eight years after the operation, recurrent GISTs were identified as multiple recurrent peritoneal GISTs in the upper right abdomen and pelvic cavity. We administered tyrosine kinase inhibitors, but they achieved poor effects. After failure of the standard treatment, PIMI was administered and achieved a partial response in the patient. The highest reduction rate was 32.7%. After PIMI failed, we performed multiplex gene panel testing, which revealed the PDGFRA D842V mutation. CONCLUSIONS We report the first case of long-term response to PIMI in PDGFRA D842V mutant GIST. Pimitespib may be effective for treating GIST harboring this mutation by inhibiting HSP90.
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Affiliation(s)
- Ryugo Teranishi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2-E2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Tsuyoshi Takahashi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2-E2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Yukinori Kurokawa
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2-E2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Takuro Saito
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2-E2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Kazuyoshi Yamamoto
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2-E2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Kotaro Yamashita
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2-E2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Koji Tanaka
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2-E2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Tomoki Makino
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2-E2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Kiyokazu Nakajima
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2-E2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2-E2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2-E2 Yamadaoka, Suita, Osaka, 565-0871, Japan
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Catalano F, Cremante M, Dalmasso B, Pirrone C, Lagodin D’Amato A, Grassi M, Comandini D. Molecular Tailored Therapeutic Options for Advanced Gastrointestinal Stromal Tumors (GISTs): Current Practice and Future Perspectives. Cancers (Basel) 2023; 15:cancers15072074. [PMID: 37046734 PMCID: PMC10093725 DOI: 10.3390/cancers15072074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 03/23/2023] [Accepted: 03/28/2023] [Indexed: 04/03/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are one of the most common mesenchymal tumors characterized by different molecular alterations that lead to specific clinical presentations and behaviors. In the last twenty years, thanks to the discovery of these mutations, several new treatment options have emerged. This review provides an extensive overview of GISTs’ molecular pathways and their respective tailored therapeutic strategies. Furthermore, current treatment strategies under investigation and future perspectives are analyzed and discussed.
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Affiliation(s)
- Fabio Catalano
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Malvina Cremante
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Bruna Dalmasso
- Genetica dei Tumori Rari, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | - Chiara Pirrone
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
| | | | - Massimiliano Grassi
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
- Correspondence:
| | - Danila Comandini
- Medical Oncology Unit 1, IRCCS Ospedale Policlinico San Martino, 16132 Genoa, Italy
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Masucci MT, Motti ML, Minopoli M, Di Carluccio G, Carriero MV. Emerging Targeted Therapeutic Strategies to Overcome Imatinib Resistance of Gastrointestinal Stromal Tumors. Int J Mol Sci 2023; 24:6026. [PMID: 37046997 PMCID: PMC10094678 DOI: 10.3390/ijms24076026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/17/2023] [Accepted: 03/19/2023] [Indexed: 04/14/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common malignant mesenchymal neoplasms of the gastrointestinal tract. The gold standard for the diagnosis of GISTs is morphologic analysis with an immunohistochemical evaluation plus genomic profiling to assess the mutational status of lesions. The majority of GISTs are driven by gain-of-function mutations in the proto-oncogene c-KIT encoding the tyrosine kinase receptor (TKR) known as KIT and in the platelet-derived growth factor-alpha receptor (PDGFRA) genes. Approved therapeutics are orally available as tyrosine kinase inhibitors (TKIs) targeting KIT and/or PDGFRA oncogenic activation. Among these, imatinib has changed the management of patients with unresectable or metastatic GISTs, improving their survival time and delaying disease progression. Nevertheless, the majority of patients with GISTs experience disease progression after 2-3 years of imatinib therapy due to the development of secondary KIT mutations. Today, based on the identification of new driving oncogenic mutations, targeted therapy and precision medicine are regarded as the new frontiers for GISTs. This article reviews the most important mutations in GISTs and highlights their importance in the current understanding and treatment options of GISTs, with an emphasis on the most recent clinical trials.
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Affiliation(s)
- Maria Teresa Masucci
- Preclinical Models of Tumor Progression Unit, Istituto Nazionale Tumori IRCCS ‘Fondazione G. Pascale’, 80131 Naples, Italy
| | - Maria Letizia Motti
- Preclinical Models of Tumor Progression Unit, Istituto Nazionale Tumori IRCCS ‘Fondazione G. Pascale’, 80131 Naples, Italy
- Department of Movement Sciences and Wellbeing, University “Parthenope”, 80133 Naples, Italy
| | - Michele Minopoli
- Preclinical Models of Tumor Progression Unit, Istituto Nazionale Tumori IRCCS ‘Fondazione G. Pascale’, 80131 Naples, Italy
| | - Gioconda Di Carluccio
- Preclinical Models of Tumor Progression Unit, Istituto Nazionale Tumori IRCCS ‘Fondazione G. Pascale’, 80131 Naples, Italy
| | - Maria Vincenza Carriero
- Preclinical Models of Tumor Progression Unit, Istituto Nazionale Tumori IRCCS ‘Fondazione G. Pascale’, 80131 Naples, Italy
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Viganò M, La Milia M, Grassini MV, Pugliese N, De Giorgio M, Fagiuoli S. Hepatotoxicity of Small Molecule Protein Kinase Inhibitors for Cancer. Cancers (Basel) 2023; 15:cancers15061766. [PMID: 36980652 PMCID: PMC10046041 DOI: 10.3390/cancers15061766] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 03/09/2023] [Accepted: 03/11/2023] [Indexed: 03/17/2023] Open
Abstract
Small molecule protein kinase inhibitors (PKIs) have become an effective strategy for cancer patients. However, hepatotoxicity is a major safety concern of these drugs, since the majority are reported to increase transaminases, and few of them (Idelalisib, Lapatinib, Pazopanib, Pexidartinib, Ponatinib, Regorafenib, Sunitinib) have a boxed label warning. The exact rate of PKI-induced hepatoxicity is not well defined due to the fact that the majority of data arise from pre-registration or registration trials on fairly selected patients, and the post-marketing data are often based only on the most severe described cases, whereas most real practice studies do not include drug-related hepatotoxicity as an end point. Although these side effects are usually reversible by dose adjustment or therapy suspension, or by switching to an alternative PKI, and fatality is uncommon, all patients undergoing PKIs should be carefully pre-evaluated and monitored. The management of this complication requires an individually tailored reappraisal of the risk/benefit ratio, especially in patients who are responding to therapy. This review reports the currently available data on the risk and management of hepatotoxicity of all the approved PKIs.
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Affiliation(s)
- Mauro Viganò
- Gastroenterology Hepatology and Transplantation Unit, ASST Papa Giovanni XXIII, 24127 Bergamo, Italy
- Correspondence: ; Tel.: +39-035-2674259; Fax: +39-035-2674964
| | - Marta La Milia
- Gastroenterology Hepatology and Transplantation Unit, ASST Papa Giovanni XXIII, 24127 Bergamo, Italy
| | - Maria Vittoria Grassini
- Gastroenterology Hepatology and Transplantation Unit, ASST Papa Giovanni XXIII, 24127 Bergamo, Italy
- Section of Gastroenterology & Hepatology, Department of Health Promotion Sciences Maternal and Infant Care, Internal Medicine and Medical Specialties, PROMISE, University of Palermo, 90127 Palermo, Italy
| | - Nicola Pugliese
- Department of Gastroenterology, Division of Internal Medicine and Hepatology, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy
| | - Massimo De Giorgio
- Gastroenterology Hepatology and Transplantation Unit, ASST Papa Giovanni XXIII, 24127 Bergamo, Italy
| | - Stefano Fagiuoli
- Gastroenterology Hepatology and Transplantation Unit, ASST Papa Giovanni XXIII, 24127 Bergamo, Italy
- Gastroenterology, Department of Medicine, University of Milan Bicocca, 20126 Milan, Italy
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Unk M, Jezeršek Novaković B, Novaković S. Molecular Mechanisms of Gastrointestinal Stromal Tumors and Their Impact on Systemic Therapy Decision. Cancers (Basel) 2023; 15:1498. [PMID: 36900287 PMCID: PMC10001062 DOI: 10.3390/cancers15051498] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 02/23/2023] [Accepted: 02/24/2023] [Indexed: 03/08/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are soft tissue sarcomas that mostly derive from Cajal cell precursors. They are by far the most common soft tissue sarcomas. Clinically, they present as gastrointestinal malignancies, most often with bleeding, pain, or intestinal obstruction. They are identified using characteristic immunohistochemical staining for CD117 and DOG1. Improved understanding of the molecular biology of these tumors and identification of oncogenic drivers have altered the systemic treatment of primarily disseminated disease, which is becoming increasingly complex. Gain-of-function mutations in KIT or PDGFRA genes represent the driving mutations in more than 90% of all GISTs. These patients exhibit good responses to targeted therapy with tyrosine kinase inhibitors (TKIs). Gastrointestinal stromal tumors lacking the KIT/PDGFRA mutations, however, represent distinct clinico-pathological entities with diverse molecular mechanisms of oncogenesis. In these patients, therapy with TKIs is hardly ever as effective as for KIT/PDGFRA-mutated GISTs. This review provides an outline of current diagnostics aimed at identifying clinically relevant driver alterations and a comprehensive summary of current treatments with targeted therapies for patients with GISTs in both adjuvant and metastatic settings. The role of molecular testing and the selection of the optimal targeted therapy according to the identified oncogenic driver are reviewed and some future directions are proposed.
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Affiliation(s)
- Mojca Unk
- Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia
- Division of Medical Oncology, Institute of Oncology Ljubljana, Zaloška 2, 1000 Ljubljana, Slovenia
| | - Barbara Jezeršek Novaković
- Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia
- Division of Medical Oncology, Institute of Oncology Ljubljana, Zaloška 2, 1000 Ljubljana, Slovenia
| | - Srdjan Novaković
- Department of Molecular Diagnostics, Institute of Oncology Ljubljana, 1000 Ljubljana, Slovenia
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Thirasastr P, Somaiah N. Emerging Data on the Safety and Efficacy of Ripretinib for the Treatment of Gastrointestinal Stromal Tumors. Clin Exp Gastroenterol 2023; 16:11-19. [PMID: 36798653 PMCID: PMC9926989 DOI: 10.2147/ceg.s351839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 01/18/2023] [Indexed: 02/18/2023] Open
Abstract
In patients with gastrointestinal stromal tumors (GIST), systemic treatment after disease progression on imatinib is challenging. Sunitinib and regorafenib are approved in the second- and third-line setting, respectively, with activity against certain secondary mutations with comparatively much lower response rates and survival increment compared to imatinib. All three of these drugs were serendipitously found to have activity in GIST, starting with imatinib, which was formulated for its ability to inhibit BCR-ABL in chronic myelogenous leukemia. Ripretinib is a drug that was specifically developed as a more potent KIT tyrosine kinase inhibitor (TKI), with broad-spectrum activity against the mutations encountered in GIST. Encouraging responses in early and later lines of treatment in the Phase 1 trial of ripretinib in GIST led to the rapid development of this novel drug. In a Phase 3 randomized clinical trial with cross-over, ripretinib demonstrated superior PFS and overall survival (OS) in 4th-line treatment and beyond compared to placebo. This established 150 mg once daily ripretinib as the standard of care in this setting. Ripretinib is generally well tolerated, with common adverse effects of hair loss, diarrhea, cramps, fatigue and nausea. The favorable safety profile and efficacy of ripretinib prompted its evaluation in a randomized phase 3 trial in the 2nd-line treatment setting. However, it did not result in a longer PFS duration than sunitinib. Although the efficacy of ripretinib in this unselected patient population was not significantly different from that of sunitinib, the tolerability profile was better. This review article aims to review the efficacy and tolerability profile of ripretinib, together with its role in the setting of unresectable or metastatic GIST.
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Affiliation(s)
- Prapassorn Thirasastr
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Neeta Somaiah
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA,Correspondence: Neeta Somaiah, Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0450, Houston, TX, 77030, USA, Tel +1 713 792-3626, Email
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Liu Q, Li S, Qiu Y, Zhang J, Rios FJ, Zou Z, Touyz RM. Cardiovascular toxicity of tyrosine kinase inhibitors during cancer treatment: Potential involvement of TRPM7. Front Cardiovasc Med 2023; 10:1002438. [PMID: 36818331 PMCID: PMC9936099 DOI: 10.3389/fcvm.2023.1002438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2022] [Accepted: 01/18/2023] [Indexed: 02/05/2023] Open
Abstract
Receptor tyrosine kinases (RTKs) are a class of membrane spanning cell-surface receptors that transmit extracellular signals through the membrane to trigger diverse intracellular signaling through tyrosine kinases (TKs), and play important role in cancer development. Therapeutic approaches targeting RTKs such as vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), and platelet-derived growth factor receptor (PDGFR), and TKs, such as c-Src, ABL, JAK, are widely used to treat human cancers. Despite favorable benefits in cancer treatment that prolong survival, these tyrosine kinase inhibitors (TKIs) and monoclonal antibodies targeting RTKs are also accompanied by adverse effects, including cardiovascular toxicity. Mechanisms underlying TKI-induced cardiovascular toxicity remain unclear. The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitously expressed chanzyme consisting of a membrane-based ion channel and intracellular α-kinase. TRPM7 is a cation channel that regulates transmembrane Mg2+ and Ca2+ and is involved in a variety of (patho)physiological processes in the cardiovascular system, contributing to hypertension, cardiac fibrosis, inflammation, and atrial arrhythmias. Of importance, we and others demonstrated significant cross-talk between TRPM7, RTKs, and TK signaling in different cell types including vascular smooth muscle cells (VSMCs), which might be a link between TKIs and their cardiovascular effects. In this review, we summarize the implications of RTK inhibitors (RTKIs) and TKIs in cardiovascular toxicities during anti-cancer treatment, with a focus on the potential role of TRPM7/Mg2+ as a mediator of RTKI/TKI-induced cardiovascular toxicity. We also describe the important role of TRPM7 in cancer development and cardiovascular diseases, and the interaction between TRPM7 and RTKs, providing insights for possible mechanisms underlying cardiovascular disease in cancer patients treated with RTKI/TKIs.
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Affiliation(s)
- Qing Liu
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China,Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Suyao Li
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yuran Qiu
- State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, National Research Center for Translational Medicine at Shanghai, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Jiayu Zhang
- Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Francisco J. Rios
- Research Institute of McGill University Health Centre, McGill University, Montreal, QC, Canada
| | - Zhiguo Zou
- Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China,Zhiguo Zou ✉
| | - Rhian M. Touyz
- Research Institute of McGill University Health Centre, McGill University, Montreal, QC, Canada,*Correspondence: Rhian M. Touyz ✉
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Sargsyan A, Kucharczyk MA, Jones RL, Constantinidou A. Ripretinib for the treatment of adult patients with advanced gastrointestinal stromal tumors. Expert Rev Gastroenterol Hepatol 2023; 17:119-127. [PMID: 36644853 DOI: 10.1080/17474124.2023.2167711] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
INTRODUCTION Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. Imatinib mesylate revolutionized the management of advanced/metastatic GIST, and remains the standard first-line therapy in this setting. Upon development of secondary resistance, sunitinib and regorafenib are used as subsequent treatments, although clinical benefit is often non-durable. Ripretinib is a type II kinase inhibitor targeting KIT and PDGFRA mutations and resistance through switching active I and inactive II forms. AREAS COVERED This drug profile article provides an overview of the current state of the art treatment algorithm for advanced/metastatic GIST, focusing on the role of ripretinib in the fourth-line setting as defined by currently available clinical trials evidence. The mechanism of action, the safety profile, efficacy, and clinical application of ripretinib are presented. In addition, the Phase I study (NCT02571036) through which the optimal dose was established and the Phase III trials that assessed the efficacy and safety of ripretinib as fourth- (INVICTUS) and second-line treatment (INTRIGUE) are presented. EXPERT OPINION Ripretinib is a safe and an effective therapy for the fourth-line setting in advanced/metastatic GIST. Future studies should evaluate combination schedules and the identification of markers predictive of benefit from ripretinib.
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Affiliation(s)
- Amalya Sargsyan
- Medical School, University of Cyprus, Nicosia, Cyprus.,Department of Medical Oncology, Bank of Cyprus Oncology Centre, Nicosia, Cyprus
| | | | - Robin L Jones
- NHS Trust, Royal Marsden Hospital, London, UK.,Division of Clinical Studies, The Institute of Cancer Research, London, UK
| | - Anastasia Constantinidou
- Medical School, University of Cyprus, Nicosia, Cyprus.,Department of Medical Oncology, Bank of Cyprus Oncology Centre, Nicosia, Cyprus
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Baa AK, Rastogi S, Fernandes S, Shrivastava S, Yadav R, Barwad A, Shamim SA, Dash NR. Insights into the medical management of gastrointestinal stromal tumours: lessons learnt from a dedicated gastrointestinal stromal tumour clinic in North India. Ecancermedicalscience 2023; 17:1497. [PMID: 36816783 PMCID: PMC9937073 DOI: 10.3332/ecancer.2023.1497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Indexed: 01/18/2023] Open
Abstract
Background The advent of molecular driver alterations has brought in a revolutionary transformation in the treatment landscape of gastrointestinal stromal tumour (GIST). However, there is a paucity of data regarding mutational testing prevalence and associated outcomes from India. Methods It was a retrospective study. We reviewed the case records of all patients diagnosed with GIST in a tertiary care centre from 2015 to 2021. The clinicopathological, mutational analysis and treatment plans were recorded. The study cohort was characterised by descriptive statistics. Results Our study included 120 patients with a median age of 53 years (range: 28-77), with a male preponderance of 2:1. The most common site of the primary was the stomach (50%), followed by the small intestine (37%), with 55.8% of the patients having disseminated disease at presentation with a predominance of liver metastasis (67%). The prevalence of mutational analysis among patients prior to referral was 4%. 60.8% of the patients at our clinic had mutational analysis performed, and unavailability of analysis in the rest was due to financial constraints (12.5%), exhaustion of tissue (7.5%), reluctance to repeat biopsy (4.1%) and low-risk patients. We report c-kit in the majority (52%), platelet-derived growth factor receptor (PDGFR) in 19.2% and wild type in 16.4% along with the rarer subtypes: succinate dehydrogenase (SDH)-deficient GIST in 10.9% and Neurotrophic tyrosine receptor kinase (NTRK) fusion in 1.3%. Four of the eight SDH-deficient GIST patients had germline mutations (50%). The knowledge of driver mutations led to a change of treatment in 39.7% (29/73), i.e. stoppage of tyrosine kinase inhibitor (TKI) in 3, switch of TKI in 23, increase in TKI dose in 2 and upfront surgery in 1. The most common change was the use of sunitinib and regorafenib in patients with SDH-deficient GIST. Conclusion Our study is one of the largest comprehensive series describing the clinical and mutational profile of GIST from India. The mutation testing rates at primary care centres continue to be low. Despite the hurdles, a large percentage of our patients underwent molecular testing, aiding in therapeutic decision-making.
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Affiliation(s)
- Annie Kanchan Baa
- Department of Medical Oncology, Dr B R Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Sameer Rastogi
- Department of Medical Oncology, Dr B R Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Sanal Fernandes
- Department of Medical Oncology, Dr B R Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Shakti Shrivastava
- Department of Medical Oncology, Dr B R Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Rajni Yadav
- Department of Pathology, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Adarsh Barwad
- Department of Pathology, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Shamim A Shamim
- Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Nihar Ranjan Dash
- Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi 110029, India
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Basu D, Pal R, Sarkar M, Barma S, Halder S, Roy H, Nandi S, Samadder A. To Investigate Growth Factor Receptor Targets and Generate Cancer Targeting Inhibitors. Curr Top Med Chem 2023; 23:2877-2972. [PMID: 38164722 DOI: 10.2174/0115680266261150231110053650] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 09/20/2023] [Accepted: 10/02/2023] [Indexed: 01/03/2024]
Abstract
Receptor tyrosine kinase (RTK) regulates multiple pathways, including Mitogenactivated protein kinases (MAPKs), PI3/AKT, JAK/STAT pathway, etc. which has a significant role in the progression and metastasis of tumor. As RTK activation regulates numerous essential bodily processes, including cell proliferation and division, RTK dysregulation has been identified in many types of cancers. Targeting RTK is a significant challenge in cancer due to the abnormal upregulation and downregulation of RTK receptors subfamily EGFR, FGFR, PDGFR, VEGFR, and HGFR in the progression of cancer, which is governed by multiple RTK receptor signalling pathways and impacts treatment response and disease progression. In this review, an extensive focus has been carried out on the normal and abnormal signalling pathways of EGFR, FGFR, PDGFR, VEGFR, and HGFR and their association with cancer initiation and progression. These are explored as potential therapeutic cancer targets and therefore, the inhibitors were evaluated alone and merged with additional therapies in clinical trials aimed at combating global cancer.
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Affiliation(s)
- Debroop Basu
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
| | - Riya Pal
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, IndiaIndia
| | - Maitrayee Sarkar
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
| | - Soubhik Barma
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
| | - Sumit Halder
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
| | - Harekrishna Roy
- Nirmala College of Pharmacy, Vijayawada, Guntur, Andhra Pradesh, India
| | - Sisir Nandi
- Global Institute of Pharmaceutical Education and Research (Affiliated to Uttarakhand Technical University), Kashipur, 244713, India
| | - Asmita Samadder
- Cell and Developmental Biology Special, Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
- Cytogenetics and Molecular Biology Lab., Department of Zoology, University of Kalyani, Kalyani, Nadia, 741235, India
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Khosroyani HM, Klug LR, Heinrich MC. TKI Treatment Sequencing in Advanced Gastrointestinal Stromal Tumors. Drugs 2023; 83:55-73. [PMID: 36607590 PMCID: PMC10029090 DOI: 10.1007/s40265-022-01820-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/23/2022] [Indexed: 01/07/2023]
Abstract
Prior to the early 2000s, patients with advanced gastrointestinal stromal tumors (GIST) had very poor prognoses owing to a lack of effective therapies. The development of tyrosine kinase inhibitors at the turn of the century significantly improved the overall survival for patients with GIST. The resounding success of imatinib in the first clinical trial of a tyrosine kinase inhibitor to treat GIST led to its approval for first-line therapy for advanced GIST; this study was open to all comers and not restricted to any GIST subtype(s). The trials that led to the approvals of second-, third-, and fourth-line therapy for advanced GIST were also open to all patients with advanced/metastatic GIST. Only in retrospect do we realize the role that the molecular subtypes played in the results observed in these studies. In this review, we discuss the studies that led to the US Food and Drug Administration approval of imatinib (first line), sunitinib (second line), regorafenib (third line), and ripretinib (fourth line) for advanced KIT-mutant GIST. In addition, we review how information about GIST molecular subtypes has been used to accelerate the approval of other targeted therapies for non-KIT mutant GIST, leading to the approval of five additional drugs indicated for the treatment of specific GIST molecular subtypes. We also discuss how our understanding of the molecular subtypes will play a role in the next generation of therapeutic approaches for treating advanced GIST.
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Affiliation(s)
- Homma M Khosroyani
- Portland VA Health Care System and Knight Cancer Institute, Oregon Health & Science University, R&D-19, 3710 SW US Veterans Hospital Road, Portland, OR, 97239, USA
| | - Lillian R Klug
- Portland VA Health Care System and Knight Cancer Institute, Oregon Health & Science University, R&D-19, 3710 SW US Veterans Hospital Road, Portland, OR, 97239, USA
| | - Michael C Heinrich
- Portland VA Health Care System and Knight Cancer Institute, Oregon Health & Science University, R&D-19, 3710 SW US Veterans Hospital Road, Portland, OR, 97239, USA.
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