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Dedousis D, Gadra E, Van Galen J, von Mehren M. Recent Advances in Succinate Dehydrogenase Deficient Gastrointestinal Stromal Tumor Systemic Therapies. Curr Treat Options Oncol 2025; 26:227-240. [PMID: 40045030 DOI: 10.1007/s11864-025-01304-w] [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: 02/15/2025] [Indexed: 04/02/2025]
Abstract
OPINION STATEMENT Gastrointestinal stromal tumors (GIST) are the most common gastrointestinal soft tissue sarcomas, with an incidence of about 15 cases per million person-years. Approximately 15% of GIST develop due to succinate dehydrogenase deficiency (SDH-Def), and such tumors do not respond well to the tyrosine kinase inhibitors (TKIs) used to treat other GIST. Due to its indolent nature SDH-Def GIST can often be surveilled if asymptomatic. In our current practice we typically treat advanced symptomatic SDH-Def GIST with the anti-angiogenic TKIs, sequentially treating with sunitinib, regorafenib and pazopanib. This practice is based on limited data. This systematic review provides an update on new data (12/21/2021 to 9/26/2024) for systemic treatment of SDH-Def GIST, both with agents generally used to treat other GIST subtypes and with agents approved in other malignancies. Olverembatinib and rogaratinib have shown promising activity in pre-clinical models and small SDH-Def GIST cohorts. Other agents whose benefits are explored here include the immune checkpoint inhibitors (ICI) ipilimumab and nivolumab and temozolomide, whether as monotherapy or in combination with INBRX-109 (a pro-apoptotic antibody) or olaparib. Additional research into TKI agents with anti-vascular endothelial growth factor receptor (VEGFR) and anti-fibroblast growth factor receptor (FGFR) activity in this clinical setting is needed. Patients with SDH-Def will benefit more broadly from ongoing explorations of treatments with alternative mechanisms of action, especially those that exploit cellular pathways involved in SDH-Def GIST tumorigenesis.
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Affiliation(s)
- Demitrios Dedousis
- Department of Hematology/Oncology, Fox Chase Cancer Center, 333 Cottman Avenue , Philadelphia, PA, 19111, USA
| | - Elyse Gadra
- Lewis Katz School of Medicine, Temple University, Philadelphia, USA
| | - Joseph Van Galen
- Department of Hematology/Oncology, Fox Chase Cancer Center, 333 Cottman Avenue , Philadelphia, PA, 19111, USA
| | - Margaret von Mehren
- Department of Hematology/Oncology, Fox Chase Cancer Center, 333 Cottman Avenue , Philadelphia, PA, 19111, USA.
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Ingham M, Allred JB, Chen L, Das B, Kochupurakkal B, Gano K, George S, Attia S, Burgess MA, Seetharam M, Boikos SA, Bui N, Chen JL, Close JL, Cote GM, Thaker PH, Ivy SP, Bose S, D'Andrea A, Marino-Enriquez A, Shapiro GI, Schwartz GK. Phase II Study of Olaparib and Temozolomide for Advanced Uterine Leiomyosarcoma (NCI Protocol 10250). J Clin Oncol 2023; 41:4154-4163. [PMID: 37467452 PMCID: PMC10852403 DOI: 10.1200/jco.23.00402] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 04/11/2023] [Accepted: 06/05/2023] [Indexed: 07/21/2023] Open
Abstract
PURPOSE Uterine leiomyosarcoma (uLMS) is an aggressive subtype of soft-tissue sarcoma with frequent metastatic relapse after curative surgery. Chemotherapy provides limited benefit for advanced disease. Multiomics profiling studies have identified homologous recombination deficiency in uLMS. In preclinical studies where olaparib and temozolomide provided modest activity, the combination was highly effective for inhibiting uLMS tumor growth. PATIENTS AND METHODS NCI Protocol 10250 is a single-arm, open-label, multicenter, phase II study evaluating olaparib and temozolomide in advanced uLMS. Patients with progression on ≥1 prior line received temozolomide 75 mg/m2 orally once daily with olaparib 200 mg orally twice a day both on days 1-7 in 21-day cycles. The primary end point was the best objective response rate (ORR) within 6 months. A one-stage binomial design was used. If ≥5 of 22 responded, the treatment would be considered promising (93% power; α = .06). All patients underwent paired biopsies that were evaluated with whole-exome sequencing (WES)/RNAseq and a RAD51 foci formation assay. RESULTS Twenty-two patients were evaluable. The median age was 55 years, and 59% had received three or more prior lines. Best ORR within 6 months was 23% (5 of 22). The overall ORR was 27% (6 of 22). The median progression-free survival (mPFS) was 6.9 months (95% CI, 5.4 months to not estimable). Hematologic toxicity was common (grade 3/4 neutropenia: 75%; thrombocytopenia: 32%) but manageable with dose modification. Five of 16 (31%) of tumors contained a deleterious homologous recombination gene alteration by WES, and 9 of 18 (50%) were homologous recombination-deficient by the RAD51 assay. In an exploratory analysis, mPFS was prolonged for patients with homologous recombination-deficient versus homologous recombination-proficient tumors (11.2 v 5.4 months, P = .05) by RAD51. CONCLUSION Olaparib and temozolomide met the prespecified primary end point and provided meaningful clinical benefit in patients with advanced, pretreated uLMS.
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Affiliation(s)
| | | | - Li Chen
- Molecular Characterization Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD
| | - Biswasjit Das
- Molecular Characterization Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD
| | | | | | - Suzanne George
- Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA
| | | | - Melissa A. Burgess
- University of Pittsburgh Medical Center, Hillman Cancer Center, Pittsburgh, PA
| | | | | | - Nam Bui
- Stanford University, Stanford, CA
| | | | - Julia L. Close
- University of Florida/UF Health Cancer Center, Gainesville, FL
| | | | | | | | - Sminu Bose
- Columbia University Irving Medical Center, New York, NY
| | - Alan D'Andrea
- Center for DNA Damage Repair, Dana-Farber Cancer Institute, Boston, MA
- Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA
| | - Adrian Marino-Enriquez
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Geoffrey I. Shapiro
- Center for DNA Damage Repair, Dana-Farber Cancer Institute, Boston, MA
- Dana-Farber Cancer Institute/Harvard Medical School, Boston, MA
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Li B, Chen H, Yang S, Chen F, Xu L, Li Y, Li M, Zhu C, Shao F, Zhang X, Deng C, Zeng L, He Y, Zhang C. Advances in immunology and immunotherapy for mesenchymal gastrointestinal cancers. Mol Cancer 2023; 22:71. [PMID: 37072770 PMCID: PMC10111719 DOI: 10.1186/s12943-023-01770-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 03/29/2023] [Indexed: 04/20/2023] Open
Abstract
Mesenchymal gastrointestinal cancers are represented by the gastrointestinal stromal tumors (GISTs) which occur throughout the whole gastrointestinal tract, and affect human health and economy globally. Curative surgical resections and tyrosine kinase inhibitors (TKIs) are the main managements for localized GISTs and recurrent/metastatic GISTs, respectively. Despite multi-lines of TKIs treatments prolonged the survival time of recurrent/metastatic GISTs by delaying the relapse and metastasis of the tumor, drug resistance developed quickly and inevitably, and became the huge obstacle for stopping disease progression. Immunotherapy, which is typically represented by immune checkpoint inhibitors (ICIs), has achieved great success in several solid tumors by reactivating the host immune system, and been proposed as an alternative choice for GIST treatment. Substantial efforts have been devoted to the research of immunology and immunotherapy for GIST, and great achievements have been made. Generally, the intratumoral immune cell level and the immune-related gene expressions are influenced by metastasis status, anatomical locations, driver gene mutations of the tumor, and modulated by imatinib therapy. Systemic inflammatory biomarkers are regarded as prognostic indicators of GIST and closely associated with its clinicopathological features. The efficacy of immunotherapy strategies for GIST has been widely explored in pre-clinical cell and mouse models and clinical experiments in human, and some patients did benefit from ICIs. This review comprehensively summarizes the up-to-date advancements of immunology, immunotherapy and research models for GIST, and provides new insights and perspectives for future studies.
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Affiliation(s)
- Bo Li
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China
| | - Hui Chen
- Shenzhen Key Laboratory of Chinese Medicine Active Substance Screening and Translational Research, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China
| | - Shaohua Yang
- Guangdong-Hong Kong-Macau University Joint Laboratory of Digestive Cancer Research, Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China
| | - Feng Chen
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China
| | - Liangliang Xu
- Shenzhen Key Laboratory for Drug Addiction and Medication Safety, Department of Ultrasound, Peking University Shenzhen Hospital, Shenzhen, 518036, China
| | - Yan Li
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China
| | - Mingzhe Li
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China
| | - Chengming Zhu
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China
| | - Fangyuan Shao
- MOE Frontiers Science Center for Precision Oncology, Faculty of Health Sciences, Institute of Translational Medicine, Cancer Center, University of Macau, Macau SAR, 999078, China
| | - Xinhua Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-Sen University, No. 58 Zhongshan Road, Guangzhou, 510080, China
| | - Chuxia Deng
- MOE Frontiers Science Center for Precision Oncology, Faculty of Health Sciences, Institute of Translational Medicine, Cancer Center, University of Macau, Macau SAR, 999078, China.
| | - Leli Zeng
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China.
| | - Yulong He
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China.
| | - Changhua Zhang
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China.
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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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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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von Mehren M, Kane JM, Agulnik M, Bui MM, Carr-Ascher J, Choy E, Connelly M, Dry S, Ganjoo KN, Gonzalez RJ, Holder A, Homsi J, Keedy V, Kelly CM, Kim E, Liebner D, McCarter M, McGarry SV, Mesko NW, Meyer C, Pappo AS, Parkes AM, Petersen IA, Pollack SM, Poppe M, Riedel RF, Schuetze S, Shabason J, Sicklick JK, Spraker MB, Zimel M, Hang LE, Sundar H, Bergman MA. Soft Tissue Sarcoma, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2022; 20:815-833. [PMID: 35830886 PMCID: PMC10186762 DOI: 10.6004/jnccn.2022.0035] [Citation(s) in RCA: 176] [Impact Index Per Article: 58.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Soft tissue sarcomas (STS) are rare malignancies of mesenchymal cell origin that display a heterogenous mix of clinical and pathologic characteristics. STS can develop from fat, muscle, nerves, blood vessels, and other connective tissues. The evaluation and treatment of patients with STS requires a multidisciplinary team with demonstrated expertise in the management of these tumors. The complete NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Soft Tissue Sarcoma provide recommendations for the diagnosis, evaluation, and treatment of extremity/superficial trunk/head and neck STS, as well as retroperitoneal/intra-abdominal STS, desmoid tumors, and rhabdomyosarcoma. This portion of the NCCN Guidelines discusses general principles for the diagnosis and treatment of retroperitoneal/intra-abdominal STS, outlines treatment recommendations, and reviews the evidence to support the guidelines recommendations.
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Affiliation(s)
| | | | | | | | | | - Edwin Choy
- Massachusetts General Hospital Cancer Center
| | - Mary Connelly
- The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | - Sarah Dry
- UCLA Jonsson Comprehensive Cancer Center
| | | | | | | | - Jade Homsi
- UT Southwestern Simmons Comprehensive Cancer Center
| | | | | | - Edward Kim
- Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance
| | - David Liebner
- The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | | | | | - Nathan W Mesko
- Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | - Christian Meyer
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
| | - Alberto S Pappo
- St. Jude Children's Research Hospital/The University of Tennessee Health Science Center
| | | | | | - Seth M Pollack
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | | | | | - Jacob Shabason
- Abramson Cancer Center at the University of Pennsylvania
| | | | - Matthew B Spraker
- Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
| | - Melissa Zimel
- UCSF Helen Diller Family Comprehensive Cancer Center; and
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Noh JJ, Cho YJ, Ryu JY, Choi JJ, Hwang JR, Choi JY, Lee JW. Anti-cancer activity of the combination of cabozantinib and temozolomide in uterine sarcoma. Clin Cancer Res 2022; 28:3850-3861. [PMID: 35727598 DOI: 10.1158/1078-0432.ccr-22-0985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 05/11/2022] [Accepted: 06/16/2022] [Indexed: 11/16/2022]
Abstract
PURPOSE To evaluate the anti-cancer effects of cabozantinib, temozolomide, and their combination in uterine sarcoma cell lines and mouse xenograft models. EXPERIMENTAL DESIGN Human uterine sarcoma cell lines (SK-LMS-1, SK-UT-1, MES-SA, and SKN) were used to evaluate the anti-cancer activity of cabozantinib, temozolomide, and their combination. The optimal dose of each drug was determined by MTT assay. Cell proliferation and apoptosis were assessed 48 hours and 72 hours after the drug treatments. The tumor weights were measured in an SK-LMS-1 xenograft mouse model and a patient-derived xenograft (PDX) model of leiomyosarcoma treated with cabozantinib, temozolomide, or both. RESULTS Given individually, cabozantinib and temozolomide each significantly decreased the growth and viability of cells. This inhibitory effect was more pronounced when cabozantinib (0.50 µM) and temozolomide (0.25 mM or 0.50 mM) were co-administered (p-value < 0.05). The combination of the drugs also significantly increased apoptosis in all cells. Moreover, this effect was consistently observed in patient-derived leiomyosarcoma cells. In vivo studies with SK-LMS-1 cell xenografts and the PDX model with leiomyosarcoma demonstrated that combined treatment with cabozantinib (5 mg/kg/day, per os administration) and temozolomide (5 mg/kg/day, per os administration) synergistically decreased tumor growth (both p-values < 0.05). CONCLUSION The addition of cabozantinib to temozolomide offers synergistic anti-cancer effects in uterine sarcoma cell lines and xenograft mouse models, including PDX. These results warrant further investigation in a clinical trial.
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Affiliation(s)
- Joseph J Noh
- Samsung Medical Center, Seoul, Korea (South), Republic of
| | - Young-Jae Cho
- Samsung Medical Center, Seoul, Seoul, Korea (South), Republic of
| | - Ji-Yoon Ryu
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (South), Republic of
| | - Jung-Joo Choi
- Samsung Medical Center, Seoul, Korea (South), Republic of
| | - Jae Ryoung Hwang
- Sungkyunkwan Univeristy School of Medicine, Seoul, Korea (South), Republic of
| | - Ju-Yeon Choi
- Samsung Medical Center, Korea (South), Republic of
| | - Jeong-Won Lee
- Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (South), Republic of
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Kasper B, D'Ambrosio L, Davis EJ, Ingham M, Broto JM, Trent JC, van Houdt WJ, Van Tine BA. What Clinical Trials Are Needed for Treatment of Leiomyosarcoma? Curr Treat Options Oncol 2022; 23:439-449. [PMID: 35275323 PMCID: PMC8930904 DOI: 10.1007/s11864-021-00928-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/26/2021] [Indexed: 11/27/2022]
Abstract
OPINION STATEMENT Leiomyosarcoma is one of the most common subtypes of soft tissue sarcomas accounting for approximately 20% of sarcomas. As leiomyosarcoma patients frequently develop metastatic disease, effective systemic therapies are needed to improve clinical outcomes. The overall activity of the currently available conventional systemic therapies and the prognosis of patients with advanced and/or metastatic disease are poor. As such, the treatment of this patient population remains challenging. As a result, there is a clear unmet medical need, and designing and performing meaningful clinical studies are of utmost importance to improve the prognosis of this patient group. Therefore, the aim of this review is to briefly summarize state-of-the-art treatments for leiomyosarcoma patients and to describe trial characteristics needed for informative clinical studies.
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Affiliation(s)
- Bernd Kasper
- Mannheim University Medical Center, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, D-68167, Mannheim, Germany.
| | | | - Elizabeth J Davis
- Department of Internal Medicine, Division of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, USA
| | | | - Javier Martin Broto
- Medical Oncology Department, University Hospital Fundacion Jimenez Diaz, Madrid, Spain
| | - Jonathan C Trent
- Sylvester Comprehensive Cancer Center, University of Miami, Miami, USA
| | - Winan J van Houdt
- Department of Surgical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Brian A Van Tine
- Siteman Cancer Center, Washington University in St. Louis, St. Louis, USA
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Casali PG, Blay JY, Abecassis N, Bajpai J, Bauer S, Biagini R, Bielack S, Bonvalot S, Boukovinas I, Bovee JVMG, Boye K, Brodowicz T, Buonadonna A, De Álava E, Dei Tos AP, Del Muro XG, Dufresne A, Eriksson M, Fedenko A, Ferraresi V, Ferrari A, Frezza AM, Gasperoni S, Gelderblom H, Gouin F, Grignani G, Haas R, Hassan AB, Hindi N, Hohenberger P, Joensuu H, Jones RL, Jungels C, Jutte P, Kasper B, Kawai A, Kopeckova K, Krákorová DA, Le Cesne A, Le Grange F, Legius E, Leithner A, Lopez-Pousa A, Martin-Broto J, Merimsky O, Messiou C, Miah AB, Mir O, Montemurro M, Morosi C, Palmerini E, Pantaleo MA, Piana R, Piperno-Neumann S, Reichardt P, Rutkowski P, Safwat AA, Sangalli C, Sbaraglia M, Scheipl S, Schöffski P, Sleijfer S, Strauss D, Strauss SJ, Hall KS, Trama A, Unk M, van de Sande MAJ, van der Graaf WTA, van Houdt WJ, Frebourg T, Gronchi A, Stacchiotti S. Gastrointestinal stromal tumours: ESMO-EURACAN-GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2022; 33:20-33. [PMID: 34560242 DOI: 10.1016/j.annonc.2021.09.005] [Citation(s) in RCA: 313] [Impact Index Per Article: 104.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 09/01/2021] [Accepted: 09/04/2021] [Indexed: 02/06/2023] Open
Affiliation(s)
- P G Casali
- Department of Cancer Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; Department of Oncology and Hemato-oncology University of Milan, Milan, Italy
| | - J Y Blay
- Centre Leon Berard and UCBL1, Lyon, France
| | - N Abecassis
- Instituto Portugues de Oncologia de Lisboa Francisco Gentil, EPE, Lisbon, Portugal
| | - J Bajpai
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - S Bauer
- Department of Medical Oncology, Interdisciplinary Sarcoma Center, West German Cancer Center, University of Duisburg-Essen, Essen, Germany
| | - R Biagini
- Department of Oncological Orthopedics, Musculoskeletal Tissue Bank, IFO, Regina Elena National Cancer Institute, Rome, Italy
| | - S Bielack
- Klinikum Stuttgart-Olgahospital, Stuttgart, Germany
| | - S Bonvalot
- Department of Surgery, Institut Curie, Paris, France
| | | | - J V M G Bovee
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
| | - K Boye
- Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
| | - T Brodowicz
- Vienna General Hospital (AKH), Medizinische Universität Wien, Vienna, Austria
| | - A Buonadonna
- Centro di Riferimento Oncologico di Aviano, Aviano, Italy
| | - E De Álava
- Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital/CSIC/University of Sevilla/CIBERONC, Seville, Spain; Department of Normal and Pathological Cytology and Histology, School of Medicine, University of Seville, Seville, Spain
| | - A P Dei Tos
- Department of Pathology, Azienda Ospedale Università Padova, Padova, Italy
| | - X G Del Muro
- Integrated Unit ICO Hospitalet, HUB, Barcelona, Spain
| | - A Dufresne
- Département d'Oncologie Médicale, Centre Leon Berard, Lyon, France
| | - M Eriksson
- Skane University Hospital-Lund, Lund, Sweden
| | - A Fedenko
- P. A. Herzen Cancer Research Institute, Moscow, Russian Federation
| | - V Ferraresi
- Sarcomas and Rare Tumors Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - A Ferrari
- Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - A M Frezza
- Department of Cancer Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - S Gasperoni
- Department of Oncology and Robotic Surgery, Azienda Ospedaliera Universitaria Careggi, Florence, Italy
| | - H Gelderblom
- Department of Medical Oncology, Leiden University Medical Centre, Leiden, The Netherlands
| | - F Gouin
- Centre Leon-Berard Lyon, Lyon, France
| | - G Grignani
- Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Italy
| | - R Haas
- Department of Radiotherapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Radiotherapy, Leiden University Medical Centre, Leiden, The Netherlands
| | - A B Hassan
- Oxford University Hospitals NHS Foundation Trust and University of Oxford, Oxford, UK
| | - N Hindi
- Department of Medical Oncology, Fundación Jimenez Diaz, University Hospital, Advanced Therapies in Sarcoma Lab, Madrid, Spain
| | - P Hohenberger
- Mannheim University Medical Center, Mannheim, Germany
| | - H Joensuu
- Helsinki University Hospital (HUH) and University of Helsinki, Helsinki, Finland
| | - R L Jones
- Sarcoma Unit, Royal Marsden Hospital and Institute of Cancer Research, London, UK
| | - C Jungels
- Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - P Jutte
- University Medical Center Groningen, Groningen, The Netherlands
| | - B Kasper
- Mannheim University Medical Center, Mannheim, Germany
| | - A Kawai
- Department of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - K Kopeckova
- University Hospital Motol, Prague, Czech Republic
| | - D A Krákorová
- Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - A Le Cesne
- Department of Cancer Medicine, Gustave Roussy, Villejuif, France
| | - F Le Grange
- Department of Oncology, University College London Hospitals NHS Foundation Trust (UCLH), London, UK
| | - E Legius
- Department for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - A Leithner
- Department of Orthopaedics and Trauma, Medical University of Graz, Graz, Austria
| | - A Lopez-Pousa
- Medical Oncology Department, Hospital Universitario Santa Creu i Sant Pau, Barcelona, Spain
| | - J Martin-Broto
- Department of Medical Oncology, Fundación Jimenez Diaz, University Hospital, Advanced Therapies in Sarcoma Lab, Madrid, Spain
| | - O Merimsky
- Aviv Sourasky Medical Center (Ichilov), Tel Aviv, Israel
| | - C Messiou
- Department of Radiology, Royal Marsden Hospital and Institute of Cancer Research, London, UK
| | - A B Miah
- Department of Oncology, Royal Marsden Hospital and Institute of Cancer Research, London, UK
| | - O Mir
- Department of Ambulatory Cancer Care, Gustave Roussy, Villejuif, France
| | - M Montemurro
- Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - C Morosi
- Department of Radiology, IRCCS Foundation National Cancer Institute, Milan, Italy
| | - E Palmerini
- Department of Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - M A Pantaleo
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria, di Bologna, Bologna, Italy
| | - R Piana
- Azienda Ospedaliero, Universitaria Città della Salute e della Scienza di Torino, Turin, Italy
| | | | - P Reichardt
- Helios Klinikum Berlin Buch, Berlin, Germany
| | - P Rutkowski
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - A A Safwat
- Aarhus University Hospital, Aarhus, Denmark
| | - C Sangalli
- Department of Radiotherapy, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - M Sbaraglia
- Department of Pathology, Azienda Ospedale Università Padova, Padova, Italy
| | - S Scheipl
- Department of Orthopaedics and Trauma, Medical University of Graz, Graz, Austria
| | - P Schöffski
- Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium
| | - S Sleijfer
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - D Strauss
- Department of Surgery, Royal Marsden Hospital, London, UK
| | - S J Strauss
- Department of Oncology, University College London Hospitals NHS Foundation Trust (UCLH), London, UK
| | - K Sundby Hall
- Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
| | - A Trama
- Department of Research, Evaluative Epidemiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - M Unk
- Institute of Oncology of Ljubljana, Ljubljana, Slovenia
| | - M A J van de Sande
- Department of Orthopedic Surgery, Leiden University Medical Center, Leiden, The Netherlands
| | - W T A van der Graaf
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands; Department of Medical Oncology, the Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - W J van Houdt
- Department of Surgical Oncology, the Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - T Frebourg
- Department of Genetics, Normandy Center for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France
| | - A Gronchi
- Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori and University of Milan, Milan, Italy
| | - S Stacchiotti
- Department of Cancer Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
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10
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Tan H, Zuo L, Ma S, Wang D, Li R, Yang Y, Liu W, Chi Y. Efficacy and Safety of Epirubicin Combined with Temozolomide for Treatment of Advanced Leiomyosarcoma. Cancer Manag Res 2021; 13:9075-9083. [PMID: 34916850 PMCID: PMC8672029 DOI: 10.2147/cmar.s342213] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 11/24/2021] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Leiomyosarcoma (LMS) accounts for 24% of all soft tissue sarcomas (STSs) and this STS subtype has high metastatic potential. Previous studies indicated the best median progression-free survival (mPFS) time was 9.2 months and the best overall response rate (ORR) was 30.9%. We evaluated the efficacy and safety of epirubicin combined with temozolomide (EPI-TMZ) for treatment of advanced LMS. METHODS This was a retrospective review of the records of patients with advanced LMS at the National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. All patients initiated EPI-TMZ treatment between January 2018 and December 2020. RESULTS We examined 15 patients who received EPI-TMZ for LMS. This was a first-line treatment in 6 patients, a second- or third-line treatment in 7 patients, and a fourth-line treatment in 2 patients. At the time of data cutoff (April 25, 2021), the median PFS was 10 months, 1 patient had clinical complete response (cCR), 7 had partial response (PR), and 7 had stable disease (SD). The overall response rate (ORR) was 53.3% (8/15) and the disease control rate (DCR) was 100.0% (15/15). The most common treatment-related adverse effects were leukopenia, neutropenia, thrombocytopenia, anemia, nausea, vomiting, fatigue, and oral mucositis. One patient had severe adverse effect (febrile neutropenia), but there were no treatment-related deaths. CONCLUSION EPI-TMZ is potentially effective for treatment of advanced LMS, and the adverse effects appear tolerable. EPI-TMZ provided better outcomes than reported in previous studies of other treatments for advanced LMS.
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Affiliation(s)
- Huijing Tan
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China
| | - Lijie Zuo
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China
- Beijing Chaoyang Sanhuan Cancer Hospital, Beijing, 100021, People’s Republic of China
| | - Shutao Ma
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China
| | - Dingyuan Wang
- Department of Breast Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China
| | - Rui Li
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China
- Beijing Chaoyang Sanhuan Cancer Hospital, Beijing, 100021, People’s Republic of China
| | - Yiqi Yang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China
- Beijing Chaoyang Sanhuan Cancer Hospital, Beijing, 100021, People’s Republic of China
| | - Weili Liu
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China
- Beijing Chaoyang Sanhuan Cancer Hospital, Beijing, 100021, People’s Republic of China
| | - Yihebali Chi
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China
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11
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Yebra M, Bhargava S, Kumar A, Burgoyne AM, Tang CM, Yoon H, Banerjee S, Aguilera J, Cordes T, Sheth V, Noh S, Ustoy R, Li S, Advani SJ, Corless CL, Heinrich MC, Kurzrock R, Lippman SM, Fanta PT, Harismendy O, Metallo C, Sicklick JK. Establishment of Patient-Derived Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumor Models for Predicting Therapeutic Response. Clin Cancer Res 2021; 28:187-200. [PMID: 34426440 DOI: 10.1158/1078-0432.ccr-21-2092] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 08/19/2021] [Accepted: 08/19/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract, with mutant succinate dehydrogenase (SDH) subunits (A-D) comprising less than 7.5% (i.e., 150-200/year) of new cases annually in the United States. Contrary to GISTs harboring KIT or PDGFRA mutations, SDH-mutant GISTs affect adolescents/young adults, often metastasize, and are frequently resistant to tyrosine kinase inhibitors (TKI). Lack of human models for any SDH-mutant tumors, including GIST, has limited molecular characterization and drug discovery. EXPERIMENTAL DESIGN We describe methods for establishing novel patient-derived SDH-mutant (mSDH) GIST models and interrogated the efficacy of temozolomide on these tumor models in vitro and in clinical trials of patients with mSDH GIST. RESULTS Molecular and metabolic characterization of our patient-derived mSDH GIST models revealed that these models recapitulate the transcriptional and metabolic hallmarks of parent tumors and SDH deficiency. We further demonstrate that temozolomide elicits DNA damage and apoptosis in our mSDH GIST models. Translating our in vitro discovery to the clinic, a cohort of patients with SDH-mutant GIST treated with temozolomide (n = 5) demonstrated a 40% objective response rate and 100% disease control rate, suggesting that temozolomide represents a promising therapy for this subset of GIST. CONCLUSIONS We report the first methods to establish patient-derived mSDH tumor models, which can be readily employed for understanding patient-specific tumor biology and treatment strategies. We also demonstrate that temozolomide is effective in patients with mSDH GIST who are refractory to existing chemotherapeutic drugs (namely, TKIs) in clinic for GISTs, bringing a promising treatment option for these patients to clinic.
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Affiliation(s)
- Mayra Yebra
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Surgery, Division of Surgical Oncology, University of California San Diego, San Diego, California
| | - Shruti Bhargava
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Surgery, Division of Surgical Oncology, University of California San Diego, San Diego, California
| | - Avi Kumar
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Bioengineering, University of California San Diego, La Jolla, California
| | - Adam M Burgoyne
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Medicine, Division of Hematology Oncology, University of California San Diego, San Diego, California
| | - Chih-Min Tang
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Surgery, Division of Surgical Oncology, University of California San Diego, San Diego, California
| | - Hyunho Yoon
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Surgery, Division of Surgical Oncology, University of California San Diego, San Diego, California
| | - Sudeep Banerjee
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Surgery, Division of Surgical Oncology, University of California San Diego, San Diego, California
| | - Joseph Aguilera
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Radiation Medicine and Applied Sciences, University of California San Diego, San Diego, California
| | - Thekla Cordes
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Bioengineering, University of California San Diego, La Jolla, California
| | - Vipul Sheth
- Department of Radiology, Stanford University, Palo Alto, Stanford, California
| | - Sangkyu Noh
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Surgery, Division of Surgical Oncology, University of California San Diego, San Diego, California
| | - Rowan Ustoy
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Surgery, Division of Surgical Oncology, University of California San Diego, San Diego, California
| | - Sam Li
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Surgery, Division of Surgical Oncology, University of California San Diego, San Diego, California
| | - Sunil J Advani
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Radiation Medicine and Applied Sciences, University of California San Diego, San Diego, California
| | | | - Michael C Heinrich
- Hematology/Medical Oncology, Portland VA Health Care System and OHSU Knight Cancer Institute, Portland, Oregon
| | - Razelle Kurzrock
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Medicine, Division of Hematology Oncology, University of California San Diego, San Diego, California.,Center for Personalized Cancer Therapy, University of California San Diego Moores Cancer Center, San Diego, California
| | - Scott M Lippman
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Medicine, Division of Hematology Oncology, University of California San Diego, San Diego, California.,Center for Personalized Cancer Therapy, University of California San Diego Moores Cancer Center, San Diego, California
| | - Paul T Fanta
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Medicine, Division of Hematology Oncology, University of California San Diego, San Diego, California.,Center for Personalized Cancer Therapy, University of California San Diego Moores Cancer Center, San Diego, California
| | - Olivier Harismendy
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Medicine, Division of Biomedical Informatics, University of California San Diego, San Diego, California
| | - Christian Metallo
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Bioengineering, University of California San Diego, La Jolla, California.,Diabetes and Endocrinology Research Center, University of California San Diego, La Jolla, California.,Institute of Engineering in Medicine, University of California San Diego, La Jolla, California
| | - Jason K Sicklick
- Moores Cancer Center, University of California San Diego, La Jolla, California. .,Department of Surgery, Division of Surgical Oncology, University of California San Diego, San Diego, California.,Center for Personalized Cancer Therapy, University of California San Diego Moores Cancer Center, San Diego, California
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12
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Nannini M, Rizzo A, Indio V, Schipani A, Astolfi A, Pantaleo MA. Targeted therapy in SDH-deficient GIST. Ther Adv Med Oncol 2021; 13:17588359211023278. [PMID: 34262616 PMCID: PMC8246492 DOI: 10.1177/17588359211023278] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 05/19/2021] [Indexed: 12/30/2022] Open
Abstract
The medical management of advanced gastrointestinal stromal tumors (GIST) has improved with the development of tyrosine kinase inhibitors (TKIs) targeting KIT and PDGFRA mutations. However, approximately 5-10% of GIST lack KIT and PDGFRA mutations, and about a half are deficient in succinate dehydrogenase (SDH) that promotes carcinogenesis by the cytoplasmic accumulation of succinate. This rare group of GIST primarily occurs in the younger patients than other subtypes, and is frequently associated with hereditary syndromes. The role of TKIs in patients with SDH-deficient GIST is controversial, with conflicting results; thus, there is an urgent need to uncover the disease mechanisms, treatment patterns, and responses to systemic therapy among these patients. Here, based on an extensive literature search, we have provided a rigorous overview of the current evidence on the medical treatment of SDH-deficient GIST.
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Affiliation(s)
- Margherita Nannini
- Division of Oncology, IRCSS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Alessandro Rizzo
- Department of Experimental, Diagnostic and Specialized Medicine, University of Bologna, Bologna, Italy
| | - Valentina Indio
- "Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna, Italy
| | - Angela Schipani
- Department of Experimental, Diagnostic and Specialized Medicine, University of Bologna, Bologna, Italy
| | - Annalisa Astolfi
- Department of Translational Medicine, University of Ferrara, Via Fossato di Mortara 70, Ferrara 44121, Italy
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13
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Lou L, Zhang W, Li J, Wang Y. Abnormal MGMT Promoter Methylation in Gastrointestinal Stromal Tumors: Genetic Susceptibility and Association with Clinical Outcome. Cancer Manag Res 2020; 12:9941-9952. [PMID: 33116851 PMCID: PMC7568426 DOI: 10.2147/cmar.s269388] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 09/25/2020] [Indexed: 01/22/2023] Open
Abstract
Purpose KIT/PDGFRA wild-type (WT) gastrointestinal stromal tumors (GISTs) represent a heterogeneous subgroup of GISTs that lack KIT or PDGFRA mutations and possess distinct genetic alterations and primary resistance to imatinib. Succinate dehydrogenase (SDH)-deficient GISTs comprise the largest subpopulation of WT GISTs that are characterized by loss-of-function of SDH. O6-methylguanine-DNA methyltransferase (MGMT) is a specific DNA repair enzyme that has been identified as a predictor of positive treatment response to alkylating agents in a variety of cancers. The aim of this study was to evaluate the expression of MGMT and the prevalence of MGMT promoter methylation in GISTs and to determine the association between MGMT promoter methylation and clinicopathological characteristics and clinical outcomes. Patients and Methods A heterogeneous cohort of 137 primary GISTs that confirmed by immunohistochemistry and KIT/PDGFRA mutation analysis were retrospectively selected and analyzed for MGMT expression and MGMT promoter methylation using immunohistochemical staining and methylation-specific PCR (MSP). A concordance analysis between MGMT promoter methylation and clinicopathological characteristics and prognosis was also performed. Results A total of 44.5% (65/137) of GIST patients displayed loss of MGMT protein expression, and 10.9% (15/137) of these patients exhibited MGMT promoter methylation. However, no significant correlation was observed between the loss of MGMT protein expression and MGMT promoter methylation. WT GISTs possessing an epithelioid or mixed phenotype, particularly those that were SDH-deficient, displayed a markedly higher prevalence of MGMT promoter methylation compared to that in KIT/PDGFRA mutated GISTs. Moreover, MGMT promoter methylation was identified as a potential independent prognostic factor for OS and DFS in patients with GIST. Conclusion MGMT promoter methylation is particularly frequent in SDH-deficient GISTs and in WT GISTs possessing an epithelioid/mixed phenotype, and knowledge of this methylation status may offer a novel potential therapeutic option for WT GISTs.
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Affiliation(s)
- Liping Lou
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Wendi Zhang
- Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Jun Li
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Yu Wang
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
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14
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Neppala P, Banerjee S, Fanta PT, Yerba M, Porras KA, Burgoyne AM, Sicklick JK. Current management of succinate dehydrogenase-deficient gastrointestinal stromal tumors. Cancer Metastasis Rev 2020; 38:525-535. [PMID: 31773431 DOI: 10.1007/s10555-019-09818-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Gastrointestinal stromal tumors (GISTs) are increasingly recognized as having diverse biology. With the development of tyrosine kinase inhibitors molecularly matched to oncogenic KIT and PDGFRA mutations, GISTs have become a quintessential model for precision oncology. However, about 5-10% of GIST lack these driver mutations and are deficient in succinate dehydrogenase (SDH), an enzyme that converts succinate to fumarate. SDH deficiency leads to accumulation of succinate, an oncometabolite that promotes tumorigenesis. SDH-deficient GISTs are clinically unique in that they generally affect younger patients and are associated with GIST-paraganglioma hereditary syndrome, also known as Carney-Stratakis Syndrome. SDH-deficient GISTs are generally resistant to tyrosine-kinase inhibitors, the standard treatment for advanced or metastatic GIST. Thus, surgical resection is the mainstay of treatment for localized disease, but recurrence is common. Clinical trials are currently underway investigating systemic agents for treatment of advanced SDH-deficient GIST. However, further studies are warranted to improve our understanding of SDH-deficient GIST disease biology, natural history, surgical approaches, and novel therapeutics.
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Affiliation(s)
- Pushpa Neppala
- UC San Diego School of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Sudeep Banerjee
- Division of Surgical Oncology, Department of Surgery, UC San Diego Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.,Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Paul T Fanta
- Center for Personalized Cancer Therapy, UC San Diego Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.,Division of Hematology-Oncology, Department of Medicine, UC San Diego Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Mayra Yerba
- Division of Surgical Oncology, Department of Surgery, UC San Diego Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Kevin A Porras
- UC San Diego School of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Adam M Burgoyne
- Division of Hematology-Oncology, Department of Medicine, UC San Diego Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
| | - Jason K Sicklick
- Division of Surgical Oncology, Department of Surgery, UC San Diego Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA. .,Center for Personalized Cancer Therapy, UC San Diego Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
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15
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Bui NQ, Wang DS, Hiniker SM. Contemporary management of metastatic soft tissue sarcoma. Curr Probl Cancer 2019; 43:289-299. [DOI: 10.1016/j.currproblcancer.2019.06.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Accepted: 06/08/2019] [Indexed: 01/31/2023]
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16
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Abstract
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. With the advent of Imatinib, the treatment of gastrointestinal stromal tumor has been revolutionized as both the progression-free and overall survival rates have increased dramatically. Unfortunately, gastrointestinal stromal tumor patients on Imatinib do eventually fail due to resistance. Even though sunitinib and regorafenib have been shown to be highly effective as second- and third-line treatments, both have limited effects. New treatments are highly warranted for this reason. In this present review, 25 registered pharmacological clinical trials at ClinicalTrials.gov have been reviewed and show promising and encouraging results.
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Affiliation(s)
- Ardavan Khoshnood
- 1 Department of Clinical Sciences, Faculty of Medicine, Lund University, Lund, Sweden.,2 Department of Emergency Medicine, Skåne University Hospital Lund, Lund, Sweden
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17
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Ravegnini G, Ricci R. Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumors: Small Steps Toward Personalized Medicine? Epigenet Insights 2019; 12:2516865719842534. [PMID: 31020269 PMCID: PMC6463228 DOI: 10.1177/2516865719842534] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Accepted: 03/08/2019] [Indexed: 12/12/2022] Open
Abstract
Various molecular triggers define heterogeneous subsets of gastrointestinal stromal tumors (GISTs), differing in clinical behavior and drug sensitivity. KIT/PDGFRA-wild-type GISTs, including those succinate dehydrogenase (SDH)-deficient, are overall unresponsive to the tyrosine kinase inhibitors commonly used, fostering the development of specific alternative therapeutic strategies. Epigenetic inactivation of O6-methylguanine-DNA methyltransferase (MGMT) through promoter methylation leads to effectiveness of alkylating agents in several human cancers. SDH-deficient GISTs typically feature widespread DNA methylation. However, the actual occurrence of MGMT methylation in these tumors, potentially predisposing them to respond to alkylating drugs, has not been investigated so far. Here we discuss the recent findings concerning the occurrence of MGMT methylation in different GIST subgroups, including SDH-deficient ones, as a premise for a possible reappraisal of alkylating agents specifically targeting these small, otherwise overall chemorefractory, GIST subgroups.
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Affiliation(s)
- Gloria Ravegnini
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Riccardo Ricci
- Department of Pathology, Università Cattolica del Sacro Cuore, Rome, Italy.,UOC di Anatomia Patologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
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18
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Ricci R, Martini M, Ravegnini G, Cenci T, Milione M, Lanza P, Pierconti F, Santini D, Angelini S, Biondi A, Rosa F, Alfieri S, Clemente G, Persiani R, Cassano A, Pantaleo MA, Larocca LM. Preferential MGMT methylation could predispose a subset of KIT/PDGFRA-WT GISTs, including SDH-deficient ones, to respond to alkylating agents. Clin Epigenetics 2019; 11:2. [PMID: 30616628 PMCID: PMC6322231 DOI: 10.1186/s13148-018-0594-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 12/03/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (GISTs) constitute a small KIT/PDGFRA-WT GIST subgroup featuring DNA methylation which, although pervasive, appears nevertheless not randomly distributed. Although often indolent, these tumors are mostly chemorefractory in aggressive cases. Promoter methylation-induced O6-methylguanine DNA methyltransferase (MGMT) inactivation improves the efficacy of alkylating agents in gliomas, colorectal cancer and diffuse large B cell lymphoma. MGMT methylation has been found in some GISTs, without determining SDH status. Thirty-six GISTs were enrolled in past sarcoma trials testing alkylating agents, with negative results. Nevertheless, a possible effect on MGMT-methylated GISTs could have escaped detection, since tested GISTs were neither selected by genotype nor investigated for SDH; MGMT was studied in two cases only, revealing baseline activity; these trials were performed prior to the adoption of Choi criteria, the most sensitive for detecting GIST responses to therapy. Under these circumstances, we investigated whether MGMT methylation is preferentially found in SDH-deficient cases (identified by SDHB immunohistochemistry) by analyzing 48 pathogenetically heterogeneous GISTs by methylation-specific PCR, as a premise for possible investigations on the use of alkylating drugs in these tumors. RESULTS Nine GISTs of our series were SDH-deficient, revealing significantly enriched in MGMT-methylated cases (6/9-67%-, vs. 6/39-15%- of SDH-proficient GISTs; p = 0.004). The pathogenetically heterogeneous KIT/PDGFRA-WT GISTs were also significantly MGMT-methylated (11/24-46%-, vs. 1/24-4%- of KIT/PDGFRA-mutant cases, p = 0.002). CONCLUSIONS A subset of KIT/PDGFRA-WT GISTs, including their largest pathogenetically characterized subgroup (i.e., SDH-deficient ones), is preferentially MGMT-methylated. This finding could foster a reappraisal of alkylating agents for treating malignant cases occurring among these overall chemorefractory tumors.
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Affiliation(s)
- Riccardo Ricci
- Department of Pathology, Università Cattolica del Sacro Cuore, Largo F.Vito 1, 00168, Rome, Italy. .,UOC di Anatomia Patologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy.
| | - Maurizio Martini
- Department of Pathology, Università Cattolica del Sacro Cuore, Largo F.Vito 1, 00168, Rome, Italy.,UOC di Anatomia Patologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy
| | - Gloria Ravegnini
- Department of Pharmacy and Biotechnology, University of Bologna, via Massarenti 9, 40138, Bologna, Italy
| | - Tonia Cenci
- UOC di Anatomia Patologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy
| | - Massimo Milione
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 20100, Milan, Italy
| | - Paola Lanza
- UOC di Anatomia Patologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy
| | - Francesco Pierconti
- Department of Pathology, Università Cattolica del Sacro Cuore, Largo F.Vito 1, 00168, Rome, Italy.,UOC di Anatomia Patologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy
| | - Donatella Santini
- Pathology Unit, S.Orsola-Malpighi Hospital, University of Bologna, via Massarenti 9, 40138, Bologna, Italy
| | - Sabrina Angelini
- Department of Pharmacy and Biotechnology, University of Bologna, via Massarenti 9, 40138, Bologna, Italy
| | - Alberto Biondi
- UOC di Chirurgia Generale, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy
| | - Fausto Rosa
- UOC di Chirurgia Digestiva, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy
| | - Sergio Alfieri
- UOC di Chirurgia Digestiva, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy.,Department of Surgery, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168, Rome, Italy
| | - Gennaro Clemente
- Department of Surgery, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168, Rome, Italy.,UOC di Chirurgia Generale ed Epato-Biliare, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy
| | - Roberto Persiani
- UOC di Chirurgia Generale, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy.,Department of Surgery, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168, Rome, Italy
| | - Alessandra Cassano
- Department of Internal Medicine, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168, Rome, Italy.,UOC di Oncologia Medica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy
| | - Maria A Pantaleo
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, via Massarenti 9, 40138, Bologna, Italy
| | - Luigi M Larocca
- Department of Pathology, Università Cattolica del Sacro Cuore, Largo F.Vito 1, 00168, Rome, Italy.,UOC di Anatomia Patologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy
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19
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Kawaguchi K, Igarashi K, Miyake K, Kiyuna T, Miyake M, Singh AS, Chmielowski B, Nelson SD, Russell TA, Dry SM, Li Y, Unno M, Singh SR, Eilber FC, Hoffman RM. Patterns of sensitivity to a panel of drugs are highly individualised for undifferentiated/unclassified soft tissue sarcoma (USTS) in patient-derived orthotopic xenograft (PDOX) nude-mouse models. J Drug Target 2018; 27:211-216. [PMID: 30024282 DOI: 10.1080/1061186x.2018.1499748] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Undifferentiated/unclassified soft tissue sarcoma (USTS) is a recalcitrant disease; therefore, precise individualised therapy is needed. Toward this goal, we previously established patient-derived orthotopic xenograft (PDOX) models of USTS in nude mice. Here, we determined the extent of uniqueness of drug response in a panel on USTS PDOX models from 5 different patients. We previously showed that 3 of the 5 patients were resistant to doxorubicin (DOX) despite DOX being first-line therapy. Two weeks after orthotopic tumour implantation, PDOX mouse models were randomised into five groups: untreated control, DOX, gem-citabine/docetaxel (GEM/DOC), pazopanib (PAZ), temozolomide (TEM). Three PDOX cases were completely resistant to DOX. TEM had high efficacy for 4 USTS PDOX models, including DOX-resistant cases. GEM/DOC and PAZ were effective in three USTS PDOX. One case was completely resistant to TEM. Two cases were completely resistant to PAZ. The results showed the drug sensitivity pattern for each USTS PDOX was highly individualised and that at least one effective drug could be found for each. The PDOX model could be effective in precise individualised drug sensitivity testing which is especially important for heterogeneous cancers such as USTS, and can give the patient a greater chance to be treated with an effective drug.
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Affiliation(s)
- Kei Kawaguchi
- a AntiCancer, Inc , San Diego , CA , USA.,b Department of Surgery , University of California , San Diego , CA, USA.,c Department of Surgery, Graduate School of Medicine , Tohoku University , Sendai , Japan
| | - Kentaro Igarashi
- a AntiCancer, Inc , San Diego , CA , USA.,b Department of Surgery , University of California , San Diego , CA, USA
| | - Kentaro Miyake
- a AntiCancer, Inc , San Diego , CA , USA.,b Department of Surgery , University of California , San Diego , CA, USA
| | - Tasuku Kiyuna
- a AntiCancer, Inc , San Diego , CA , USA.,b Department of Surgery , University of California , San Diego , CA, USA
| | - Masuyo Miyake
- a AntiCancer, Inc , San Diego , CA , USA.,b Department of Surgery , University of California , San Diego , CA, USA
| | - Arun S Singh
- d Division of Hematology-Oncology , University of California , Los Angeles , CA, USA
| | - Bartosz Chmielowski
- d Division of Hematology-Oncology , University of California , Los Angeles , CA, USA
| | - Scott D Nelson
- e Department of Pathology , University of California , Los Angeles , CA, USA
| | - Tara A Russell
- f Division of Surgical Oncology , University of California , Los Angeles , CA, USA
| | - Sarah M Dry
- e Department of Pathology , University of California , Los Angeles , CA, USA
| | - Yunfeng Li
- e Department of Pathology , University of California , Los Angeles , CA, USA
| | - Michiaki Unno
- c Department of Surgery, Graduate School of Medicine , Tohoku University , Sendai , Japan
| | - Shree Ram Singh
- g Basic Research Laboratory , National Cancer Institute , Frederick , MD, USA
| | - Fritz C Eilber
- f Division of Surgical Oncology , University of California , Los Angeles , CA, USA
| | - Robert M Hoffman
- a AntiCancer, Inc , San Diego , CA , USA.,b Department of Surgery , University of California , San Diego , CA, USA
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20
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Willobee BA, Quiroz HJ, Sussman MS, Thorson CM, Sola JE, Perez EA. Current treatment strategies in pediatric gastrointestinal stromal cell tumor. Transl Gastroenterol Hepatol 2018; 3:53. [PMID: 30225387 DOI: 10.21037/tgh.2018.07.09] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 07/23/2018] [Indexed: 01/06/2023] Open
Abstract
Gastrointestinal stromal tumors (GIST) are exceedingly rare tumors in the pediatric population. As a result, many clinicians either may never see this diagnosis or will encounter it only a few times throughout their careers. Additionally, the more we discover about this disease, it becomes evident that it represents a distinct clinical entity from adult GIST. Many of the treatments and strategies used to combat the adult tumor are either ineffective or may be harmful to the pediatric population with this disease. The unique tumor biology found in pediatric GIST necessitates unique approaches and treatment strategies in order to achieve the best clinical outcome. This review aims to discuss the most recent data available on the different therapeutic modalities utilized in cases of Pediatric GIST.
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Affiliation(s)
- Brent A Willobee
- Department of Surgery, Miller School of Medicine, University of Miami, Coral Gables, FL, USA
| | - Hallie J Quiroz
- Department of Surgery, Miller School of Medicine, University of Miami, Coral Gables, FL, USA
| | - Matthew S Sussman
- Department of Surgery, Miller School of Medicine, University of Miami, Coral Gables, FL, USA
| | - Chad M Thorson
- Department of Surgery, Miller School of Medicine, University of Miami, Coral Gables, FL, USA
| | - Juan E Sola
- Department of Surgery, Miller School of Medicine, University of Miami, Coral Gables, FL, USA
| | - Eduardo A Perez
- Department of Surgery, Miller School of Medicine, University of Miami, Coral Gables, FL, USA
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21
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Recurrent Severe Hypoinsulinemic Hypoglycemia Responsive to Temozolomide and Bevacizumab in a Patient With Doege-Potter Syndrome. Am J Med Sci 2018; 356:181-184. [PMID: 30219161 DOI: 10.1016/j.amjms.2018.01.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Revised: 01/16/2018] [Accepted: 01/19/2018] [Indexed: 11/20/2022]
Abstract
Nonislet cell tumor hypoglycemia is rare. We highlight the diagnosis and treatment of recurrent severe hypoglycemia in a 49-year-old woman with malignant solitary fibrous tumor of the pleura (Doege-Potter syndrome). The clinical, laboratory and radiologic findings of the case are presented and a brief literature review is provided. Of note, imaging studies showed a large mass in the right hemithorax and pathology and immunehistochemical stains confirmed a malignant solitary fibrous tumor of the pleura. She was a poor surgical candidate owing to a large tumor burden. She was treated with a combination of temozolomide and bevacizumab to which she responded with resolution of hypoglycemia. The treatment of choice for hypoglycemia in patients with the Doege-Potter syndrome is surgical excision. We here report that a combination of temozolomide and bevacizumab may be a viable option in patients with inoperable disease.
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22
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Qin Y, Zhang HB, Ke CS, Huang J, Wu B, Wan C, Yang CS, Yang KY. Primary extraskeletal myxoid chondrosarcoma in cerebellum: A case report with literature review. Medicine (Baltimore) 2017; 96:e8684. [PMID: 29381948 PMCID: PMC5708947 DOI: 10.1097/md.0000000000008684] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
RATIONALE Extraskeletal myxoid chondrosarcoma (EMC) is a rare malignant neoplasm of which intracranial EMC is the rarest. PATIENT CONCERNS We present an unusual case report of a 41-year-old woman who was sent to the emergency department for a sudden headache and other symptoms related to increased intracranial pressure. INTERVENTIONS Emergent CT revealed an occupying lesion in the left cerebellum with surrounding edema. A complete surgical excision of the lesion through a transcortical approach was performed. After the operation, this patient received adjuvant radiotherapy and temozolomide treatment. DIAGNOSES Pathology diagnosis was an intracranial EMC. OUTCOMES The patient survives with no tumor recurrence as of the last follow-up. Progression-free survival exceeded 20 months. LESSONS We have reviewed the literature and here summarize the diagnosis and treatment options for intracranial EMC. Diagnosis and treatment options of this rare disease are discussed.
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Affiliation(s)
- You Qin
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei
| | - Hai-bo Zhang
- Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang
- People's Hospital of Hangzhou medical college, Hangzhou, Zhejiang Province
| | - Chang-Shu Ke
- Department of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jing Huang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei
| | - Bian Wu
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei
| | - Chao Wan
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei
| | - Chen-Su Yang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei
| | - Kun-Yu Yang
- Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei
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23
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Abstract
Soft tissue sarcomas are rare tumors that present with distant metastasis in up to 10% of patients. Survival has improved significantly because of advancements in histologic classification and improved management approaches. Older agents such as doxorubicin, ifosfamide, gemcitabine, and paclitaxel continue to demonstrate objective response rates from 18% to 25%. Newer agents such as trabectedin, eribulin, aldoxorubicin, and olaratumab have demonstrated improvements in progression-free survival, overall survival, or toxicity profiles. Future studies on treatment of advanced soft tissue sarcoma will continue to concentrate on reducing toxicity, personalization of therapy, and targeting novel pathways.
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Affiliation(s)
- Jennifer Y Sheng
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
| | - Sujana Movva
- Department of Hematology/Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA
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24
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Kondo T. Proteogenomics for the Study of Gastrointestinal Stromal Tumors. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2016; 926:139-151. [DOI: 10.1007/978-3-319-42316-6_9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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25
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Kissova M, Maga G, Crespan E. The human tyrosine kinase Kit and its gatekeeper mutant T670I, show different kinetic properties: Implications for drug design. Bioorg Med Chem 2016; 24:4555-4562. [PMID: 27527414 DOI: 10.1016/j.bmc.2016.07.059] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Revised: 07/22/2016] [Accepted: 07/26/2016] [Indexed: 12/31/2022]
Abstract
The tyrosine kinase Kit, a receptor for Stem Cell Factor, is involved, among others, in processes associated to cell survival, proliferation and migration. Upon physiological conditions, the activity of Kit is tightly regulated. However, primary mutations that lead to its constitutive activation are the causal oncogenic driver of gastrointestinal stromal tumours (GISTs). GISTs are known to be refractory to conventional therapies but the introduction of Imatinib, a selective inhibitor of tyrosine kinases Abl and Kit, significantly ameliorated the treatment options of GISTs patients. However, the acquisition of secondary mutations renders Kit resistant towards all available drugs. Mutation involving gatekeeper residues (such as V654a and T670I) influence both the structure and the catalytic activity of the enzyme. Therefore, detailed knowledge of the enzymatic properties of the mutant forms, in comparison with the wild type enzyme, is an important pre-requisite for the rational development of specific inhibitors. In this paper we report a thorough kinetic analysis of the reaction catalyzed by the Kit kinase and its gatekeeper mutated form T670I. Our results revealed the different mechanisms of action of these two enzymes and may open a new avenue for the future design of specific Kit inhibitors.
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Affiliation(s)
- Miroslava Kissova
- Institute of Molecular Genetics IGM-CNR, via Abbiategrasso 207, 27100 Pavia, Italy
| | - Giovanni Maga
- Institute of Molecular Genetics IGM-CNR, via Abbiategrasso 207, 27100 Pavia, Italy.
| | - Emmanuele Crespan
- Institute of Molecular Genetics IGM-CNR, via Abbiategrasso 207, 27100 Pavia, Italy.
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26
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Ben Ami E, Demetri GD. A safety evaluation of imatinib mesylate in the treatment of gastrointestinal stromal tumor. Expert Opin Drug Saf 2016; 15:571-8. [PMID: 26865352 DOI: 10.1517/14740338.2016.1152258] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION For the last 15 years, imatinib mesylate has been the first line treatment of choice for advanced (metastatic) GIST. AREAS COVERED This review describes key efficacy data on imatinib for the treatment of GIST, and focuses on safety and tolerability of imatinib, with emphasis on common adverse events management and long term toxicity profile. EXPERT OPINION Imatinib has been the standard of care for metastatic GIST and probably will continue to be so for the next few years. Still, despite dramatic responses initially, imatinib drug resistance continues to be the major factor for treatment discontinuation. The toxicity profile of imatinib has been well characterized, and although the majority of patients experience an adverse event during treatment with imatinib, these side effects are usually mild and manageable, with the majority of patients continuing treatment uninterruptedly. Early concerns regarding imatinib related cardiotoxicity in GIST have not been confirmed in large prospective randomized trials, with reports indicating a low incidence of approximately 0.2%-0.4%. Future strategies for treatment of imatinib resistant GIST will probably include novel tyrosine kinase inhibitors, combination therapies or immunotherapy.
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Affiliation(s)
- Eytan Ben Ami
- a Center for Sarcoma and Bone Oncology , Dana Farber Cancer Institute , Boston , MA , USA
| | - George D Demetri
- b Center for Sarcoma and Bone Oncology and Ludwig Center at Harvard , Dana-Farber Cancer Institute and Harvard Medical School , Boston , MA , USA
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27
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Kusabe Y, Kawashima H, Ogose A, Sasaki T, Ariizumi T, Hotta T, Endo N. Effect of temozolomide on the viability of musculoskeletal sarcoma cells. Oncol Lett 2015; 10:2511-2518. [PMID: 26622881 DOI: 10.3892/ol.2015.3506] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 06/16/2015] [Indexed: 01/22/2023] Open
Abstract
Musculoskeletal sarcomas (MSS) are a heterogeneous group of malignancies with relatively high mortality rates. The prognosis for patients with MSS is poor, with few drugs inducing measurable activity. Alkylating agents, namely ifosfamide and dacarbazine, which act nonspecifically on proliferating cells, are the typical therapy prescribed for advanced MSS. A novel alkylating agent, temozolomide (TMZ), has several advantages over existing alkylating agents. TMZ induces the formation of O6-methylguanine in DNA, thereby inducing mismatches during DNA replication and the subsequent activation of apoptotic pathways. However, due to conflicting data in the literature, the mechanism of TMZ action has remained elusive. Therefore, the present study aimed to evaluate apoptosis in MSS cells treated with TMZ, and to evaluate the correlation between TMZ action and survival pathways, including the phosphoinositide 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK)1/2 mitogen activated protein kinase (MAPK) pathways. Cell proliferation was evaluated by performing an XTT (sodium 3'-[1-(phenylaminocarbonyl)-3,4-tetrazolium]-bis (4-methoxy-6-nitro) benzene sulfonic acid hydrate) assay. Apoptotic morphological changes, for example chromatin condensation, were evaluated by fluorescence confocal microscopy. The expression of the apoptosis-associated proteins caspase-3, poly adenosine diphosphate ribose polymerase (PARP), Akt and ERK1/2, was determined by western blotting. The results of the present study indicated that, in certain MSS cells, the IC50 value was lower than that in TMZ-sensitive U-87 MG cells. Furthermore, TMZ treatment was associated with apoptotic morphological changes and the expression levels of pro-apoptotic cleaved caspase-3 and PARP were also increased in TMZ-treated MSS cells. In addition, the results indicated that PI3K/Akt and ERK1/2 MAPK were constitutively phosphorylated in MSS cells, and phosphorylation of PI3K/Akt was suppressed in certain cells, and maintained in other cells, by TMZ. These observations emphasized the plasticity of MSS cells, and suggested that this plasticity may contribute to the variance in cell sensitivity to TMZ and TMZ-resistance in MSS.
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Affiliation(s)
- Yuta Kusabe
- School of Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata 851-8510, Japan
| | - Hiroyuki Kawashima
- Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 851-8510, Japan
| | - Akira Ogose
- Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 851-8510, Japan
| | - Taro Sasaki
- Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 851-8510, Japan
| | - Takashi Ariizumi
- Department of Orthopedic Surgery, Niigata Cancer Center Hospital, Niigata 951-8566, Japan
| | - Tetsuo Hotta
- Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 851-8510, Japan
| | - Naoto Endo
- Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 851-8510, Japan
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28
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Maki RG, Blay JY, Demetri GD, Fletcher JA, Joensuu H, Martín-Broto J, Nishida T, Reichardt P, Schöffski P, Trent JC. Key Issues in the Clinical Management of Gastrointestinal Stromal Tumors: An Expert Discussion. Oncologist 2015; 20:823-30. [PMID: 26070915 DOI: 10.1634/theoncologist.2014-0471] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Accepted: 03/27/2015] [Indexed: 11/17/2022] Open
Abstract
UNLABELLED After the revelation of kinase targeting with orally available small molecules, the use of imatinib in chronic myelogenous leukemia and in gastrointestinal stromal tumor (GIST) has now become commonplace and just two of many examples of the use of kinase inhibitors in cancer. In this article, we discuss important practice points that may impact upon questions of therapy of primary and metastatic GIST, with the hope that the questions addressed in this rare solid tumor can serve as examples of what can be achieved with kinase-directed therapies in other cancers. We present cases that highlight some of the key issues in GIST management and afterward discuss both points of consensus and controversial issues in what is now recognized as one of the most common forms of sarcoma. IMPLICATIONS FOR PRACTICE The treatment of gastrointestinal stromal tumor (GIST) has become sophisticated with the availability of three approved agents in many countries and 15 years of experience with primary and metastatic disease. Important lessons from tyrosine-kinase inhibitors in GIST can be gleaned from this experience and will impact implementation of similar agents for other cancers.
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Affiliation(s)
- Robert G Maki
- Tisch Cancer Institute, Mount Sinai Medical Center, New York, New York, USA; Department of Medical Oncology, Centre Léon Bérard, Lyon, France; Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA; Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Servicio de Oncología Médica, Fundación Instituto Valenciano de Oncología, Valencia, Spain; National Cancer Center Hospital East, Department of Surgery, Kashiwa, Japan; HELIOS Klinikum Berlin-Buch, Interdisciplinary Oncology, Berlin, Germany; General Medical Oncology, Leuven Cancer Institute, University Hospital Gasthuisberg, Catholic University Leuven, Leuven, Belgium; University of Miami Sylvester Cancer Center, Sarcoma Medical Oncology Program, Miami, Florida, USA
| | - Jean-Yves Blay
- Tisch Cancer Institute, Mount Sinai Medical Center, New York, New York, USA; Department of Medical Oncology, Centre Léon Bérard, Lyon, France; Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA; Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Servicio de Oncología Médica, Fundación Instituto Valenciano de Oncología, Valencia, Spain; National Cancer Center Hospital East, Department of Surgery, Kashiwa, Japan; HELIOS Klinikum Berlin-Buch, Interdisciplinary Oncology, Berlin, Germany; General Medical Oncology, Leuven Cancer Institute, University Hospital Gasthuisberg, Catholic University Leuven, Leuven, Belgium; University of Miami Sylvester Cancer Center, Sarcoma Medical Oncology Program, Miami, Florida, USA
| | - George D Demetri
- Tisch Cancer Institute, Mount Sinai Medical Center, New York, New York, USA; Department of Medical Oncology, Centre Léon Bérard, Lyon, France; Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA; Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Servicio de Oncología Médica, Fundación Instituto Valenciano de Oncología, Valencia, Spain; National Cancer Center Hospital East, Department of Surgery, Kashiwa, Japan; HELIOS Klinikum Berlin-Buch, Interdisciplinary Oncology, Berlin, Germany; General Medical Oncology, Leuven Cancer Institute, University Hospital Gasthuisberg, Catholic University Leuven, Leuven, Belgium; University of Miami Sylvester Cancer Center, Sarcoma Medical Oncology Program, Miami, Florida, USA
| | - Jonathan A Fletcher
- Tisch Cancer Institute, Mount Sinai Medical Center, New York, New York, USA; Department of Medical Oncology, Centre Léon Bérard, Lyon, France; Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA; Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Servicio de Oncología Médica, Fundación Instituto Valenciano de Oncología, Valencia, Spain; National Cancer Center Hospital East, Department of Surgery, Kashiwa, Japan; HELIOS Klinikum Berlin-Buch, Interdisciplinary Oncology, Berlin, Germany; General Medical Oncology, Leuven Cancer Institute, University Hospital Gasthuisberg, Catholic University Leuven, Leuven, Belgium; University of Miami Sylvester Cancer Center, Sarcoma Medical Oncology Program, Miami, Florida, USA
| | - Heikki Joensuu
- Tisch Cancer Institute, Mount Sinai Medical Center, New York, New York, USA; Department of Medical Oncology, Centre Léon Bérard, Lyon, France; Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA; Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Servicio de Oncología Médica, Fundación Instituto Valenciano de Oncología, Valencia, Spain; National Cancer Center Hospital East, Department of Surgery, Kashiwa, Japan; HELIOS Klinikum Berlin-Buch, Interdisciplinary Oncology, Berlin, Germany; General Medical Oncology, Leuven Cancer Institute, University Hospital Gasthuisberg, Catholic University Leuven, Leuven, Belgium; University of Miami Sylvester Cancer Center, Sarcoma Medical Oncology Program, Miami, Florida, USA
| | - Javier Martín-Broto
- Tisch Cancer Institute, Mount Sinai Medical Center, New York, New York, USA; Department of Medical Oncology, Centre Léon Bérard, Lyon, France; Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA; Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Servicio de Oncología Médica, Fundación Instituto Valenciano de Oncología, Valencia, Spain; National Cancer Center Hospital East, Department of Surgery, Kashiwa, Japan; HELIOS Klinikum Berlin-Buch, Interdisciplinary Oncology, Berlin, Germany; General Medical Oncology, Leuven Cancer Institute, University Hospital Gasthuisberg, Catholic University Leuven, Leuven, Belgium; University of Miami Sylvester Cancer Center, Sarcoma Medical Oncology Program, Miami, Florida, USA
| | - Toshirou Nishida
- Tisch Cancer Institute, Mount Sinai Medical Center, New York, New York, USA; Department of Medical Oncology, Centre Léon Bérard, Lyon, France; Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA; Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Servicio de Oncología Médica, Fundación Instituto Valenciano de Oncología, Valencia, Spain; National Cancer Center Hospital East, Department of Surgery, Kashiwa, Japan; HELIOS Klinikum Berlin-Buch, Interdisciplinary Oncology, Berlin, Germany; General Medical Oncology, Leuven Cancer Institute, University Hospital Gasthuisberg, Catholic University Leuven, Leuven, Belgium; University of Miami Sylvester Cancer Center, Sarcoma Medical Oncology Program, Miami, Florida, USA
| | - Peter Reichardt
- Tisch Cancer Institute, Mount Sinai Medical Center, New York, New York, USA; Department of Medical Oncology, Centre Léon Bérard, Lyon, France; Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA; Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Servicio de Oncología Médica, Fundación Instituto Valenciano de Oncología, Valencia, Spain; National Cancer Center Hospital East, Department of Surgery, Kashiwa, Japan; HELIOS Klinikum Berlin-Buch, Interdisciplinary Oncology, Berlin, Germany; General Medical Oncology, Leuven Cancer Institute, University Hospital Gasthuisberg, Catholic University Leuven, Leuven, Belgium; University of Miami Sylvester Cancer Center, Sarcoma Medical Oncology Program, Miami, Florida, USA
| | - Patrick Schöffski
- Tisch Cancer Institute, Mount Sinai Medical Center, New York, New York, USA; Department of Medical Oncology, Centre Léon Bérard, Lyon, France; Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA; Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Servicio de Oncología Médica, Fundación Instituto Valenciano de Oncología, Valencia, Spain; National Cancer Center Hospital East, Department of Surgery, Kashiwa, Japan; HELIOS Klinikum Berlin-Buch, Interdisciplinary Oncology, Berlin, Germany; General Medical Oncology, Leuven Cancer Institute, University Hospital Gasthuisberg, Catholic University Leuven, Leuven, Belgium; University of Miami Sylvester Cancer Center, Sarcoma Medical Oncology Program, Miami, Florida, USA
| | - Jonathan C Trent
- Tisch Cancer Institute, Mount Sinai Medical Center, New York, New York, USA; Department of Medical Oncology, Centre Léon Bérard, Lyon, France; Dana-Farber Cancer Institute, Boston, Massachusetts, USA; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA; Helsinki University Hospital and University of Helsinki, Helsinki, Finland; Servicio de Oncología Médica, Fundación Instituto Valenciano de Oncología, Valencia, Spain; National Cancer Center Hospital East, Department of Surgery, Kashiwa, Japan; HELIOS Klinikum Berlin-Buch, Interdisciplinary Oncology, Berlin, Germany; General Medical Oncology, Leuven Cancer Institute, University Hospital Gasthuisberg, Catholic University Leuven, Leuven, Belgium; University of Miami Sylvester Cancer Center, Sarcoma Medical Oncology Program, Miami, Florida, USA
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Trent JC, Subramanian MP. Managing GIST in the imatinib era: optimization of adjuvant therapy. Expert Rev Anticancer Ther 2014; 14:1445-59. [DOI: 10.1586/14737140.2014.952284] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Hsu CH, Daldrup-Link HE, Yeom KW, Donaldson SS, Million L, Hazard FK, Rangaswami A. Successful Treatment with Temozolomide Combined with Chemoradiotherapy and Surgery of a Metastatic Undifferentiated Soft Tissue Sarcoma with Relapse in the Central Nervous System of a Young Adult. J Adolesc Young Adult Oncol 2014. [DOI: 10.1089/jayao.2013.0041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Christopher H. Hsu
- Department of Pediatric Hematology-Oncology, Stanford University, Palo Alto, California
- Division of Communicable Disease Control, California Department of Public Health, Richmond, California
| | | | - Kristen W. Yeom
- Department of Pediatric Radiology, Stanford University, Palo Alto, California
| | - Sarah S. Donaldson
- Department of Radiation Oncology, Stanford University, Palo Alto, California
| | - Lynn Million
- Department of Radiation Oncology, Stanford University, Palo Alto, California
| | | | - Arun Rangaswami
- Department of Pediatric Hematology-Oncology, Stanford University, Palo Alto, California
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Kakkar A, Kumar A, Jha P, Goyal N, Mallick S, Sharma MC, Suri A, Singh M, Kale SS, Julka PK, Sarkar C, Suri V. Meningeal hemangiopericytomas: a clinicopathological study with emphasis on MGMT (O(6) -methylguanine-DNA methyltransferase) promoter methylation status. Neuropathology 2014; 34:333-42. [PMID: 24521400 DOI: 10.1111/neup.12107] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2013] [Revised: 01/08/2014] [Accepted: 01/08/2014] [Indexed: 11/26/2022]
Abstract
Meningeal hemangiopericytomas (HPCs) are aggressive dural-based tumors, for which no prognostic or predictive marker has been identified. Gross total resection is treatment of choice, but not easily achieved; hence, alkylating agents like temozolomide (TMZ) are now being tried. O(6) -methylguanine-DNA methyltransferase (MGMT) promoter methylation has proven prognostic and predictive value in glioblastomas. This study evaluates MGMT promoter methylation in meningeal HPCs to determine its role in HPC oncogenesis and its association with patient outcome. Meningeal HPCs diagnosed between 2002 and 2011 were retrieved and clinicopathological features reviewed. MGMT promoter methylation status was assessed by methylation-specific polymerase chain reaction (MSP) and immunohistochemistry (IHC) for MGMT protein. HPCs accounted for 1.1% of all CNS tumors. Forty cases were analyzed; the majority were adults (mean age = 41.4 years). Seventy percent were primary and 30% were recurrent tumors; 60% were grade II and 40% were grade III. MGMT promoter methylation was identified in 45% of cases, including Grade II (54.2%) and Grade III (31.3%) (P = 0.203). Promoter methylation was significantly (P = 0.035) more frequent in primary (57.1%) than in recurrent (16.7%) tumors. No correlation was noted between MGMT promoter methylation by MSP and MGMT protein expression by IHC, or with progression-free survival. Thus, a significant proportion of HPCs demonstrate MGMT promoter methylation, suggesting possible susceptibility to TMZ. As promoter methylation is more frequent in primary tumors, TMZ may serve as a therapeutic option in residual primary tumors. Epigenetic inactivation of MGMT in HPCs necessitates the assessment of prognostic and predictive value of MGMT promoter methylation in HPCs in larger clinical trials.
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Affiliation(s)
- Aanchal Kakkar
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
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Boichuk S, Lee DJ, Mehalek KR, Makielski KR, Wozniak A, Seneviratne DS, Korzeniewski N, Cuevas R, Parry JA, Brown MF, Zewe J, Taguchi T, Kuan SF, Schöffski P, Debiec-Rychter M, Duensing A. Unbiased compound screening identifies unexpected drug sensitivities and novel treatment options for gastrointestinal stromal tumors. Cancer Res 2014; 74:1200-13. [PMID: 24385214 DOI: 10.1158/0008-5472.can-13-1955] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Most gastrointestinal stromal tumors (GIST) are caused by oncogenic KIT or platelet-derived growth factor receptor activation, and the small molecule kinase inhibitor imatinib mesylate is an effective first-line therapy for metastatic or unresectable GIST. However, complete remissions are rare and most patients ultimately develop resistance, mostly because of secondary mutations in the driver oncogenic kinase. Hence, there is a need for novel treatment options to delay failure of primary treatment and restore tumor control in patients who progress under therapy with targeted agents. Historic data suggest that GISTs do not respond to classical chemotherapy, but systematic unbiased screening has not been performed. In screening a compound library enriched for U.S. Food and Drug Administration (FDA)-approved chemotherapeutic agents (NCI Approved Oncology Drugs Set II), we discovered that GIST cells display high sensitivity to transcriptional inhibitors and topoisomerase II inhibitors. Mechanistically, these compounds exploited the cells' dependency on continuous KIT expression and/or intrinsic DNA damage response defects, explaining their activity in GIST. Mithramycin A, an indirect inhibitor of the SP1 transcription factor, and mitoxantrone, a topoisomerase II inhibitor, exerted significant antitumor effects in mouse xenograft models of human GIST. Moreover, these compounds were active in patient-derived imatinib-resistant primary GIST cells, achieving efficacy at clinically relevant concentrations. Taken together, our findings reveal that GIST cells have an unexpectedly high and specific sensitivity to certain types of FDA-approved chemotherapeutic agents, with immediate implications for encouraging their clinical exploration.
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Affiliation(s)
- Sergei Boichuk
- Authors' Affiliations: Cancer Virology Program, University of Pittsburgh Cancer Institute, Hillman Cancer Center; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Laboratory of Experimental Oncology, Department of General Medical Oncology; Department of Human Genetics, University Hospitals Leuven and KU Leuven, Leuven, Belgium; Molecular Urooncology, University of Heidelberg School of Medicine, Heidelberg, Germany; and Department of Anatomy, Kochi Medical School, Nankoku, Kochi, Japan
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Bex A, Kerst J, Mallo H, Van Tinteren H, Horenblas S, De Gast GC. Extended Continuous Oral Temozolomide in Patients with Progressive Metastatic Renal Cell Carcinoma Not Responding to Interferon Alpha 2b. J Chemother 2013; 17:674-8. [PMID: 16433200 DOI: 10.1179/joc.2005.17.6.674] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
The aim of the study was to evaluate the toxicity and efficacy of oral extended continuous temozolomide in patients with progressive metastatic renal cell carcinoma (RCC) not responding to immunotherapy after removal of the primary tumor. Patients with progressive metastatic RCC received protracted temozolomide 100 mg/m2 orally on days 1-21 every 28 days. Response was assessed after 2 cycles to be followed by another 2 cycles in the absence of progression. After 4 cycles only patients with further remission and acceptable toxicity were to continue. No objective responses were observed in 12 patients and the trial was stopped prematurely in stage 1. Six patients remained stable during 4 cycles of temozolomide (4 months), only one of these remained stable for another 2 months after having stopped treatment. Five patients progressed after the initial 2 cycles and one after the first cycle. Overall survival was 15.5 months (range 1-36 months). Repeated cycles of 3 weeks oral temozolomide 100 mg/m2 followed by one week rest proved tolerable though this regimen may only have limited activity against metastatic RCC.
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Affiliation(s)
- A Bex
- Division of Surgical Oncology, Urology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
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Management of gastrointestinal stromal tumors: looking beyond the knife. An update on the role of adjuvant and neoadjuvant imatinib therapy. J Gastrointest Cancer 2013; 43:547-52. [PMID: 22847491 DOI: 10.1007/s12029-012-9423-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Gastrointestinal stromal tumors (GISTs) have traditionally been treated with surgical resection alone resulting in high rates of recurrence. However, the discovery of imatinib efficacy in GIST has revolutionized its management. DISCUSSION Imatinib may be used as neoadjuvant therapy with the goal of reducing tumor size, minimizing surgical morbidity and, in some cases, rendering inoperable cases operable. In addition, imatinib use in the adjuvant setting to eradicate micrometastases and prevent recurrence has shown promising results in reducing relapse rates. Appropriate patient selection and optimal dose and duration of imatinib therapy remain undecided and require further investigation. We present a literature review and a case report of our patient with a symptomatic gastric GIST managed successfully utilizing neoadjuvant imatinib therapy, laparoscopic limited resection, and adjuvant imatinib therapy.
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Angelini S, Ravegnini G, Fletcher JA, Maffei F, Hrelia P. Clinical relevance of pharmacogenetics in gastrointestinal stromal tumor treatment in the era of personalized therapy. Pharmacogenomics 2013; 14:941-56. [DOI: 10.2217/pgs.13.63] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
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Falchook GS, Trent JC, Heinrich MC, Beadling C, Patterson J, Bastida CC, Blackman SC, Kurzrock R. BRAF mutant gastrointestinal stromal tumor: first report of regression with BRAF inhibitor dabrafenib (GSK2118436) and whole exomic sequencing for analysis of acquired resistance. Oncotarget 2013; 4:310-5. [PMID: 23470635 PMCID: PMC3712576 DOI: 10.18632/oncotarget.864] [Citation(s) in RCA: 114] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2013] [Accepted: 02/24/2013] [Indexed: 12/17/2022] Open
Abstract
Activating oncogenic mutations of BRAF have been described in patients with gastrointestinal stromal tumor (GIST), but treatment of GIST with BRAF inhibitors and mechanisms of mediating the emergence of resistance in GIST have not been reported. Dabrafenib is a potent ATP-competitive inhibitor of BRAF kinase and is highly selective for mutant BRAF in kinase panel screening, cell lines, and xenografts. We report prolonged antitumor activity in the first patient with V600E BRAF-mutated GIST who was treated with a BRAF inhibitor. Whole exome sequencing performed in tumor tissue obtained at the time of progressive disease demonstrated a somatic gain-of-function PIK3CA mutation (H1047R) as well as a CDKN2A aberration, which may have contributed to eventual resistance to treatment.
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Affiliation(s)
- G S Falchook
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
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Ridolfi C, Pasini G, Drudi F, Barzotti E, Santelmo C, Polselli A, Ravaioli A. Long lasting clinical response to chemotherapy for advanced uterine leiomyosarcoma: a case report. J Med Case Rep 2013; 7:29. [PMID: 23347560 PMCID: PMC3565880 DOI: 10.1186/1752-1947-7-29] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2012] [Accepted: 12/19/2012] [Indexed: 12/27/2022] Open
Abstract
Introduction Uterine leiomyosarcoma is one of the most frequent uterine sarcomas. In the metastatic setting it is sensitive to doxorubicin, ifosfamide, gemcitabine, docetaxel and a few other drugs, but time to progression is generally short. For this reason prognosis is often poor and there are few reports in the literature of long responders. Case presentation We report a case of a 40-year-old Caucasian woman with metastatic uterine leiomyosarcoma who began treatment six years before the presentation of this case report and for the following six years underwent ten lines of chemotherapy, achieving excellent results and a good quality of life. Among the treatments administered we observed a long response to temolozomide, an unconventional drug for this kind of disease. Conclusion Although there are few chemotherapeutic options for the management of metastatic uterine leiomyosarcoma, a small number of patients have an unexpected long lasting response to treatment. For this reason further research is needed to identify new therapeutic agents and the predictive factors for the achievement of response.
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Affiliation(s)
- Claudio Ridolfi
- Oncology Department, 'Infermi' Hospital, Via Settembrini 2, Rimini, 47923, Italy.
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Cao G, Li J, Shen L, Zhu X. Transcatheter arterial chemoembolization for gastrointestinal stromal tumors with liver metastases. World J Gastroenterol 2012; 18:6134-6140. [PMID: 23155343 PMCID: PMC3496891 DOI: 10.3748/wjg.v18.i42.6134] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2012] [Revised: 08/28/2012] [Accepted: 10/19/2012] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the efficacy and safety of transcatheter arterial chemoembolization (TACE) for gastrointestinal stromal tumor (GIST) with liver metastases after the failure of tyrosine kinase inhibitors (TKIs). METHODS Patients with histologically confirmed CD117-positive GIST with liver metastases who were resistant and/or intolerant to prior imatinib and/or sunitinib and who received TACE for at least one treatment cycle or only best supportive care and TKI reintroduction were eligible for the study. The patients were divided into two groups: those in TACE group received TACE treatment containing 5-20 mL iodized oil and 40-80 mg doxorubicin hydrochloride and TKI reintroduction or best supportive care, those in control group only received TKI reintroduction or best supportive care. The primary end-point was overall survival and the secondary end-points were, progression-free survival (PFS), response rates, and safety. RESULTS Sixty patients admitted between June 2008 and October 2011 were eligible for this study, including 22 in TACE group and 38 in control group. In the TACE group, 12 (54.5%) achieved liver partial response, 5 (22.7%) had stable disease, and 5 (22.7%) had liver progressive disease. Disease control rate of liver metastases was 77.3% in the TACE group and 39.5% in the control group. The median liver PFS in TACE group was 47.1 wk (95% CI: 23.9-70.3). The median PFS in TACE group was longer than in control group (30.0 wk, 95% CI: 20.1-39.9 vs 12.9 wk, 95% CI: 11.9-13.9) (P = 0.0001). The median overall survival in TACE group was also longer than in control group (68.5 wk, 95% CI: 57.4-79.6 vs 25.7 wk, 95% CI: 23.2-28.2) (P = 0.0001). TACE treatment significantly reduced the risk of death (hazard ratio: 0.109). Patients without extrahepatic metastases treated with TACE had significantly better prognosis. Most of the adverse events were of grade 1 or 2 and tolerable. CONCLUSION TACE is effective and well tolerated in GIST patients with liver metastases after TKI failure, and it may be an optional treatment for this disease.
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Patel S. Managing progressive disease in patients with GIST: Factors to consider besides acquired secondary tyrosine kinase inhibitor resistance. Cancer Treat Rev 2012; 38:467-72. [DOI: 10.1016/j.ctrv.2011.10.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2011] [Revised: 09/29/2011] [Accepted: 10/03/2011] [Indexed: 10/15/2022]
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Bujko M, Kowalewska M, Danska-Bidzinska A, Bakula-Zalewska E, Siedecki JA, Bidzinski M. The promoter methylation and expression of the O6-methylguanine-DNA methyltransferase gene in uterine sarcoma and carcinosarcoma. Oncol Lett 2012; 4:551-555. [PMID: 22970054 DOI: 10.3892/ol.2012.771] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2012] [Accepted: 06/08/2012] [Indexed: 11/05/2022] Open
Abstract
O6-methylguanine-DNA methyltransferase (MGMT) gene promoter hypermethylation is observed in a number of solid tumors and is correlated with the silencing of MGMT expression. In glioblastoma patients treated with the alkylating agent temozolomide, MGMT gene methylation status was shown to have predictive value in terms of prolonged overall survival. Recently, temozolomide has demonstrated promising activity in the treatment of soft tissue sarcomas, including those of the uterus. The tissue specimens involving tumor samples and normal uterine fragments were obtained from nine patients with smooth muscle uterine sarcoma, 11 with stromal uterine sarcoma and 17 with mixed uterine tumors. MGMT gene promoter methylation was analyzed by combined bisulfite restriction analysis (COBRA) while its expression levels were assessed using the real-time reverse transcription polymerase chain reaction (qRT-PCR). MGMT promoter methylation was observed in 27% of all tumor samples analyzed. When stratified by the disease type, 55.5% (5/9) of smooth muscle sarcomas, 23.5% (4/17) of mixed uterine tumor tissues and 9% (1/11) of stromal sarcomas showed MGMT methylation. The MGMT promoter methylation was associated with lower levels of gene expression in tumors when compared with those with an unmethylated promoter (P=0.0232) or normal tissues (P=0.0141). To conclude, MGMT promoter methylation and downregulation of gene expression is observed in a fraction of carcinosarcomas and non-epithelial malignant tumors of corpus uteri. The assessment of MGMT promoter methylation status may potentially identify patients who would benefit from temozolomide treatment.
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Affiliation(s)
- Mateusz Bujko
- Department of Molecular Biology, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, 02-781 Warsaw, Poland
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Eisenberg BL, Trent JC. Adjuvant and neoadjuvant imatinib therapy: current role in the management of gastrointestinal stromal tumors. Int J Cancer 2011; 129:2533-42. [PMID: 21671474 DOI: 10.1002/ijc.26234] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Although surgery remains the mainstay for the treatment of primary gastrointestinal stromal tumors (GIST), a significant number of patients experience disease recurrence within 5 years of surgery. The emergence of imatinib therapy for the treatment of patients with advanced GIST has offered unprecedented improvements in clinical outcomes for these patients. Prospective clinical trials have supported the efficacy and safety of imatinib before and after surgical resection of GIST. The American College of Surgeons Oncology Group Z9001 pivotal trial revealed that 1 year of adjuvant imatinib therapy provides significantly superior recurrence-free survival in patients with GIST after surgical resection, when compared to placebo. Additional trials and case studies have also begun to define the potential clinical benefit of imatinib in the neoadjuvant setting. Optimized risk stratification paradigms will be required to ensure the appropriate selection of patients to undergo treatment with imatinib in these settings. Risk stratification schemes are evolving that potentially will include mutation status and tumor rupture, and predictive nomograms have recently been proposed. The recent European Society of Medical Oncology and National Comprehensive Cancer Network guidelines mention use of adjuvant imatinib for ≥ 1 year in patients with KIT(+) , resectable GIST at high risk of recurrence. Moreover, the guidelines support the use of neoadjuvant imatinib in cases of limited disease if it would facilitate less extensive surgery and organ sparing. This article reviews pivotal efficacy and safety data for adjuvant imatinib and explores the potential clinical benefit of neoadjuvant imatinib in patients with GIST.
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Affiliation(s)
- Burton L Eisenberg
- Dartmouth-Hitchcock Medical Center, Norris Cotton Cancer Center, Lebanon, NH, USA
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Park MS, Patel SR, Ludwig JA, Trent JC, Conrad CA, Lazar AJ, Wang WL, Boonsirikamchai P, Choi H, Wang X, Benjamin RS, Araujo DM. Activity of temozolomide and bevacizumab in the treatment of locally advanced, recurrent, and metastatic hemangiopericytoma and malignant solitary fibrous tumor. Cancer 2011; 117:4939-47. [PMID: 21480200 PMCID: PMC3135685 DOI: 10.1002/cncr.26098] [Citation(s) in RCA: 174] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2010] [Revised: 01/20/2011] [Accepted: 01/26/2011] [Indexed: 12/14/2022]
Abstract
BACKGROUND Hemangiopericytomas and malignant solitary fibrous tumors (HPC/SFT) are rare, closely related sarcomas with unpredictable behavior that respond infrequently to chemotherapy. An optimal systemic treatment strategy for advanced HPC/SFT has not yet been identified. METHODS We retrospectively analyzed the records of 14 patients with histopathologically confirmed HPC/SFT who were treated at The University of Texas MD Anderson Cancer Center between May 2005 and June 2007. All patients were treated with temozolomide 150 mg/m(2) orally on days 1-7 and days 15-21 and bevacizumab 5 mg/kg intravenously on days 8 and 22, repeated at 28-day intervals. Computed tomography assessment of tumor size and density (Choi criteria) was used to determine the best response to therapy. The Kaplan-Meier method was used to estimate progression-free survival. RESULTS The median follow-up period was 34 months. Eleven patients (79%) achieved a Choi partial response, with a median time to response of 2.5 months. Two patients (14%) had stable disease as the best response, and 1 patient (7%) had Choi progressive disease as the best response. The estimated median progression-free survival was 9.7 months, with a 6-month progression-free rate of 78.6%. The most frequently observed toxic effect was myelosuppression. CONCLUSION Combination therapy with temozolomide and bevacizumab is a generally well-tolerated and clinically beneficial regimen for HPC/SFT patients. Additional investigation in a controlled, prospective trial is warranted.
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Affiliation(s)
- Min S Park
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77230-1402, USA.
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Penel N, Van Glabbeke M, Marreaud S, Ouali M, Blay J, Hohenberger P. Testing new regimens in patients with advanced soft tissue sarcoma: analysis of publications from the last 10 years. Ann Oncol 2011; 22:1266-1272. [DOI: 10.1093/annonc/mdq608] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Tanaka H, Sasayama T, Nishihara M, Arai A, Kawamura A, Kanomata N, Itoh T, Kohmura E. Brain metastasis of undifferentiated sarcoma and response to temozolomide treatment. Case report. Neurol Med Chir (Tokyo) 2011; 50:689-93. [PMID: 20805657 DOI: 10.2176/nmc.50.689] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
A 33-year-old woman presented with rare brain metastases from undifferentiated high-grade sarcoma manifesting as headache and vomiting. Magnetic resonance (MR) imaging demonstrated multiple tumors in the brain, subcutaneous soft tissue, and mediastinum. The patient underwent surgery, followed by chemotherapy and radiotherapy. The histological diagnosis was undifferentiated high-grade sarcoma. Radiotherapy was effective, but the brain tumors recurred 6 months later. The patient underwent high-dose methotrexate therapy, but showed no response. Promoter hypermethylation in the O(6)-methylguanine-deoxyribonucleic acid methyltransferase (MGMT) genes was detected and MGMT protein expression was negative in the recurrent tumor, so temozolomide (TMZ) salvage chemotherapy was given, and follow-up MR imaging showed tumor reduction. This case suggests that TMZ may be effective for brain metastasis of undifferentiated sarcoma without MGMT protein expression.
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Affiliation(s)
- Hirotomo Tanaka
- Department of Neurosurgery, Kobe University Graduate School of Medicine, Kobe, Hyogo
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Wang WL, Conley A, Reynoso D, Nolden L, Lazar AJ, George S, Trent JC. Mechanisms of resistance to imatinib and sunitinib in gastrointestinal stromal tumor. Cancer Chemother Pharmacol 2010; 67 Suppl 1:S15-24. [PMID: 21181476 DOI: 10.1007/s00280-010-1513-8] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2010] [Accepted: 10/26/2010] [Indexed: 12/19/2022]
Abstract
Gastrointestinal stromal tumor (GIST), the most common mesenchymal neoplasm of the GI tract and one of the most common sarcomas, is dependent on the expression of the mutated KIT or platelet-derived growth factor receptor in most cases. Imatinib mesylate potently abrogates the effects of KIT signaling by directly binding into the ATP-binding pocket of the kinase. It is becoming increasingly apparent that the binding affinity of imatinib for the receptor is dependent on the type and location of mutation. Within KIT, patients whose tumor has an exon 9 mutation are treated by many clinicians with higher doses of imatinib than those patients with mutations within exon 11. Additionally, there are over 400 unique mutations within exon 11 that may have distinctly different binding affinity for imatinib as well as other kinases. Secondary KIT mutations generally occur at a codon where imatinib binds resulting in KIT reactivation and resistance. Sunitinib malate, a second-generation KIT inhibitor is active in imatinib-resistant disease and is FDA-approved for use in this setting. In this review, we describe the biology of the genes and gene mutations responsible for GIST and discuss known and potential clinical implications.
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Affiliation(s)
- Wei-Lien Wang
- Departments of Pathology, The University of Texas, M. D. Anderson Cancer Center, Houston, TX, USA
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Synergistic induction of apoptosis by the Bcl-2 inhibitor ABT-737 and imatinib mesylate in gastrointestinal stromal tumor cells. Mol Oncol 2010; 5:93-104. [PMID: 21115411 DOI: 10.1016/j.molonc.2010.10.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2010] [Revised: 10/07/2010] [Accepted: 10/08/2010] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Although imatinib mesylate has revolutionized the management of patients with gastrointestinal stromal tumor (GIST), resistance and progression almost inevitably develop with long-term monotherapy. To enhance imatinib-induced cytotoxicity and overcome imatinib-resistance in GIST cells, we examined the antitumor effects of the pro-apoptotic Bcl-2/Bcl-x(L) inhibitor ABT-737, alone and in combination with imatinib. METHODS We treated imatinib-sensitive, GIST-T1 and GIST882, and imatinib-resistant cells with ABT-737 alone and with imatinib. We determined the anti-proliferative and apoptotic effects by cell viability assay, flow cytometric apoptosis and cell cycle analysis, immunoblotting, and nuclear morphology. Synergism was determined by isobologram analysis. RESULTS The IC(50) of single-agent ABT-737 at 72 h was 10 μM in imatinib-sensitive GIST-T1 and GIST882 cells, and 1 μM in imatinib-resistant GIST48IM cells. ABT-737 and imatinib combined synergistically in a time- and dose-dependent manner to inhibit the proliferation and induce apoptosis of all GIST cells, as evidenced by cell viability and apoptosis assays, caspase activation, PARP cleavage, and morphologic changes. Isobologram analyses revealed strongly synergistic drug interactions, with combination indices <0.5 for most ABT-737/imatinib combinations. Thus, clinically relevant in vitro concentrations of ABT-737 have single-agent antitumor activity and are synergistic in combination with imatinib. CONCLUSION We provide the first preclinical evidence that Bcl-2/Bcl-x(L) inhibition with ABT-737 synergistically enhances imatinib-induced cytotoxicity via apoptosis, and that direct engagement of apoptotic cell death may be an effective approach to circumvent imatinib-resistance in GIST.
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48
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Neoadjuvant and adjuvant imatinib treatment in gastrointestinal stromal tumor: current status and recent developments. Curr Opin Oncol 2010; 22:330-5. [PMID: 20520542 DOI: 10.1097/cco.0b013e32833aaaad] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE OF REVIEW Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract and is a paradigm of targeted therapy for solid tumors. Elucidation of the biology of GIST enabled use of imatinib, which revolutionized the prognosis of advanced GIST. Whereas surgical resection continues to be the standard of care for primary GIST, judicious and individualized use of adjuvant and neoadjuvant imatinib may enhance the potential for cure in select patients. RECENT FINDINGS Prospective trials utilizing adjuvant and neoadjuvant imatinib have established the safety and efficacy of these modalities adjunct to surgical resection. Correlative tissue studies derived from these trials have examined gene expression patterns, metabolic and radiographic response, and apoptosis during the first few days of imatinib therapy. As appropriate use of adjuvant and neoadjuvant imatinib requires proper patient selection, development of a predictive nomogram, and advances in mutational analysis represent progress toward individualized care. SUMMARY Imatinib is well tolerated and beneficial as adjuvant and neoadjuvant therapy, but its utility in these settings continues to be refined. The greatest benefit will derive from an individualized approach that considers multiple patient, drug, and tumor characteristics to assess risk and likelihood of benefit for each patient.
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49
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Inhibiting the VEGF–VEGFR pathway in angiosarcoma, epithelioid hemangioendothelioma, and hemangiopericytoma/solitary fibrous tumor. Curr Opin Oncol 2010; 22:351-5. [PMID: 20485168 DOI: 10.1097/cco.0b013e32833aaad4] [Citation(s) in RCA: 126] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Demetri GD, von Mehren M, Antonescu CR, DeMatteo RP, Ganjoo KN, Maki RG, Pisters PWT, Raut CP, Riedel RF, Schuetze S, Sundar HM, Trent JC, Wayne JD. NCCN Task Force report: update on the management of patients with gastrointestinal stromal tumors. J Natl Compr Canc Netw 2010; 101:442. [PMID: 20457867 DOI: 10.1002/jso.21485] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The standard of care for managing patients with gastrointestinal stromal tumors (GISTs) rapidly changed after the introduction of effective molecularly targeted therapies involving tyrosine kinase inhibitors (TKIs), such as imatinib mesylate and sunitinib malate. A better understanding of the molecular characteristics of GISTs have improved the diagnostic accuracy and led to the discovery of novel immunomarkers and new mechanisms of resistance to TKI therapy, which in turn have resulted in the development of novel treatment strategies. To address these issues, the NCCN organized a task force consisting of a multidisciplinary panel of experts in the fields of medical oncology, surgical oncology, molecular diagnostics, and pathology to discuss the recent advances, identify areas of future research, and recommend an optimal approach to care for patients with GIST at all stages of disease. The task force met for the first time in October 2003 and again in December 2006 and October 2009. This supplement describes the recent developments in the field of GIST as discussed at the October 2009 meeting.
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