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Min V, Corradini N, Macagno N, Orbach D, Reguerre Y, Petit P, Blay JY, Verschuur A. Gastrointestinal stromal tumours (GIST) in children: An update of this orphan disease. Bull Cancer 2025; 112:348-357. [PMID: 39455327 DOI: 10.1016/j.bulcan.2024.07.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 05/31/2024] [Accepted: 07/04/2024] [Indexed: 10/28/2024]
Abstract
BACKGROUND Gastrointestinal stromal tumours (GIST) are tumours of the digestive tract that mainly develop in adults. Recommendations for the management of GIST in pediatrics are limited. MATERIAL AND METHODS We performed an updated review of the literature serving as a basis for the development of diagnostic and therapeutic recommendations for GIST in children and young adults (YA). RESULTS GIST in pediatric population can have a sporadic presentation but occur more often in a syndromic and/or familial context. Currently more than 170 cases of sporadic GIST or in association with Carney-Stratakis syndrome or Carney's triad family cases of familial GIST have been described in children and YA. These syndromes are frequently associated with germline or somatic alterations in a sub-unit of Succinate Dehydrogenase (SDH). In contrast, the frequency of somatic KIT and PDGFRα oncogene mutations (±15%) is significantly lower as compared to adults with GIST. The recommendations for the management of children with GIST are generally comparable to those used for adult patients, although certain biological differences influence the therapeutic attitude. CONCLUSIONS International collaborations have been deployed in order to increase the clinical and biological knowledge of this orphan pathology in pediatrics.
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Affiliation(s)
- Victoria Min
- Pediatric Hematology Oncology Department, La Timone Children's Hospital, AP-HM, 264, rue St Pierre, 13385 Marseille cedex, France
| | - Nadège Corradini
- Pediatric Hematology Oncology Department, Institute of Pediatric Hematology and Oncology (IHOPe), Léon Bérard Cancer Centre, Lyon, France
| | | | - Daniel Orbach
- SIREDO Oncology Centre (Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer), PSL University, Institut Curie, Paris, France
| | - Yves Reguerre
- Pediatric Oncology Department, University Hospital Center La Reunion, Saint-Denis, Reunion
| | - Philippe Petit
- Department of pediatric and prenatal radiology, La Timone Children's Hospital, Aix Marseille University, AP-HM, 264, rue St-Pierre, 13385 Marseille cedex, France
| | - Jean-Yves Blay
- Department of Medicine, Centre Leon Berard, UNICANCER & University Lyon I, Lyon, France
| | - Arnauld Verschuur
- Pediatric Hematology Oncology Department, La Timone Children's Hospital, AP-HM, 264, rue St Pierre, 13385 Marseille cedex, France.
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Li DG, Jiang JP, Chen FY, Wu W, Fu J, Wang GH, Li YB. Insulin-like growth factor 2 targets IGF1R signaling transduction to facilitate metastasis and imatinib resistance in gastrointestinal stromal tumors. World J Gastrointest Oncol 2024; 16:3585-3599. [PMID: 39171181 PMCID: PMC11334037 DOI: 10.4251/wjgo.v16.i8.3585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 06/06/2024] [Accepted: 06/25/2024] [Indexed: 08/07/2024] Open
Abstract
BACKGROUND Gastrointestinal stromal tumors (GISTs) are typical gastrointestinal tract neoplasms. Imatinib is the first-line therapy for GIST patients. Drug resistance limits the long-term effectiveness of imatinib. The regulatory effect of insulin-like growth factor 2 (IGF2) has been confirmed in various cancers and is related to resistance to chemotherapy and a worse prognosis. AIM To further investigate the mechanism of IGF2 specific to GISTs. METHODS IGF2 was screened and analyzed using Gene Expression Omnibus (GEO: GSE225819) data. After IGF2 knockdown or overexpression by transfection, the phenotypes (proliferation, migration, invasion, apoptosis) of GIST cells were characterized by cell counting kit 8, Transwell, and flow cytometry assays. We used western blotting to evaluate pathway-associated and epithelial-mesenchymal transition (EMT)-associated proteins. We injected transfected cells into nude mice to establish a tumor xenograft model and observed the occurrence and metastasis of GIST. RESULTS Data from the GEO indicated that IGF2 expression is high in GISTs, associated with liver metastasis, and closely related to drug resistance. GIST cells with high expression of IGF2 had increased proliferation and migration, invasiveness and EMT. Knockdown of IGF2 significantly inhibited those activities. In addition, OE-IGF2 promoted GIST metastasis in vivo in nude mice. IGF2 activated IGF1R signaling in GIST cells, and IGF2/IGF1R-mediated glycolysis was required for GIST with liver metastasis. GIST cells with IGF2 knockdown were sensitive to imatinib treatment when IGF2 overexpression significantly raised imatinib resistance. Moreover, 2-deoxy-D-glucose (a glycolysis inhibitor) treatment reversed IGF2 overexpression-mediated imatinib resistance in GISTs. CONCLUSION IGF2 targeting of IGF1R signaling inhibited metastasis and decreased imatinib resistance by driving glycolysis in GISTs.
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Affiliation(s)
- De-Gang Li
- Department of Gastrointestinal and Anorectal Surgery, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, Guangxi Zhuang Autonomous Region, China
| | - Jia-Peng Jiang
- Department of Gastrointestinal and Anorectal Surgery, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, Guangxi Zhuang Autonomous Region, China
| | - Fan-Ye Chen
- Department of Gastrointestinal and Anorectal Surgery, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, Guangxi Zhuang Autonomous Region, China
| | - Wei Wu
- Department of Gastrointestinal and Anorectal Surgery, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, Guangxi Zhuang Autonomous Region, China
| | - Jun Fu
- Department of Gastrointestinal and Anorectal Surgery, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, Guangxi Zhuang Autonomous Region, China
| | - Gong-He Wang
- Department of Gastrointestinal and Anorectal Surgery, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, Guangxi Zhuang Autonomous Region, China
| | - Yu-Bo Li
- Department of Gastrointestinal and Anorectal Surgery, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning 530023, Guangxi Zhuang Autonomous Region, China
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Cohen-Gogo S, Kanwar N, Shaikh F, Baertschiger RM, Shlien A, Malkin D, Putra J, Coblentz A, Villani A, Gupta AA, Morgenstern DA. Response to Alpelisib in an Adolescent With PIK3CA-Mutated Metastatic Gastrointestinal Stromal Tumor. JCO Precis Oncol 2022; 6:e2200105. [PMID: 35917491 DOI: 10.1200/po.22.00105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Affiliation(s)
- Sarah Cohen-Gogo
- Division of Hematology/Oncology, The Hospital for Sick Children, Department of Paediatrics, University of Toronto, Toronto, ON, Canada
| | - Nisha Kanwar
- Division of Pathology and Laboratory Medicine, The Hospital for Sick Children, Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, ON, Canada
| | - Furqan Shaikh
- Division of Hematology/Oncology, The Hospital for Sick Children, Department of Paediatrics, University of Toronto, Toronto, ON, Canada
| | - Reto M Baertschiger
- Division of General and Thoracic Surgery, The Hospital for Sick Children, Department of Surgery, University of Toronto, Toronto, ON, Canada
| | - Adam Shlien
- Division of Pathology and Laboratory Medicine, The Hospital for Sick Children, Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, ON, Canada
| | - David Malkin
- Division of Hematology/Oncology, The Hospital for Sick Children, Department of Paediatrics, University of Toronto, Toronto, ON, Canada
| | - Juan Putra
- Department of Pathology, Boston Children's Hospital, Boston, MA
| | - Ailish Coblentz
- Diagnostic Imaging, The Hospital for Sick Children, Toronto, ON, Canada
| | - Anita Villani
- Division of Hematology/Oncology, The Hospital for Sick Children, Department of Paediatrics, University of Toronto, Toronto, ON, Canada
| | - Abha A Gupta
- Division of Hematology/Oncology, The Hospital for Sick Children, Department of Paediatrics, University of Toronto, Toronto, ON, Canada
| | - Daniel A Morgenstern
- Division of Hematology/Oncology, The Hospital for Sick Children, Department of Paediatrics, University of Toronto, Toronto, ON, Canada
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Pitsava G, Settas N, Faucz FR, Stratakis CA. Carney Triad, Carney-Stratakis Syndrome, 3PAS and Other Tumors Due to SDH Deficiency. Front Endocrinol (Lausanne) 2021; 12:680609. [PMID: 34012423 PMCID: PMC8126684 DOI: 10.3389/fendo.2021.680609] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 04/12/2021] [Indexed: 12/20/2022] Open
Abstract
Succinate dehydrogenase (SDH) is a key respiratory enzyme that links Krebs cycle and electron transport chain and is comprised of four subunits SDHA, SDHB, SDHC and SDHD. All SDH-deficient tumors are caused by or secondary to loss of SDH activity. As many as half of the familial cases of paragangliomas (PGLs) and pheochromocytomas (PHEOs) are due to mutations of the SDHx subunits. Gastrointestinal stromal tumors (GISTs) associated with SDH deficiency are negative for KIT/PDGFRA mutations and present with distinctive clinical features such as early onset (usually childhood or adolescence) and almost exclusively gastric location. SDH-deficient GISTs may be part of distinct clinical syndromes, Carney-Stratakis syndrome (CSS) or dyad and Carney triad (CT). CSS is also known as the dyad of GIST and PGL; it affects both genders equally and is inherited in an autosomal dominant manner with incomplete penetrance. CT is a very rare disease; PGL, GIST and pulmonary chondromas constitute CT which shows female predilection and may be a mosaic disorder. Even though there is some overlap between CT and CSS, as both are due to SDH deficiency, CSS is caused by inactivating germline mutations in genes encoding for the SDH subunits, while CT is mostly caused by a specific pattern of methylation of the SDHC gene and may be due to germline mosaicism of the responsible genetic defect.
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Affiliation(s)
- Georgia Pitsava
- Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institutes of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
| | - Nikolaos Settas
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
| | - Fabio R. Faucz
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
- *Correspondence: Fabio R. Faucz,
| | - Constantine A. Stratakis
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
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Li Y, Wu X, Gao F, Wang X. MiR-197-3p regulates endothelial cell proliferation and migration by targeting IGF1R and BCL2 in Kawasaki disease. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2019; 12:4181-4192. [PMID: 31933818 PMCID: PMC6949791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Accepted: 09/27/2019] [Indexed: 06/10/2023]
Abstract
BACKGROUND Kawasaki disease (KD) is a multisystemic vasculitis syndrome. Accumulating evidences indicated that microRNAs play a critical role in KD. However, the mechanism was still not fully understood. The study aimed to research the functions of microRNA-197-3p (miR-197-3p) in the progression of KD. METHODS Level of miR-197-3p was detected by quantitative polymerase chain reaction (qRT-PCR) in acute KD serum. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay was performed to determine cell proliferation in HCAECs. Cell apoptosis was evaluated by flow cytometry. In addition, transwell assay was used to identify the migration capacity of HCAECs in vitro. The expression of insulin-like growth factor type 1 receptor (IGF1R), B cell lymphoma 2 (BCL2), apoptosis-relative of Cleaved-caspase 3 (C-caspase 3) and Cleaved-PARP (C-PARP), as well as transition-relative of E-cadherin, N-cadherin, and Vimentin were measured by western blot assay. Lastly, dual-luciferase reporter assay was employed to verify the relationship between miR-197-3p and IGF1R or BCL2 in vitro. RESULTS Level of miR-197-3p was higher in Acute KD samples than that of healthy control and convalescent KD samples. Mechanistically, the role of miR-197-3p was exerted through directly targeting IGF1R and BCL2 in KD serum-induced HCAECs. Functionally, the inhibiting effect on cell apoptosis as well as promoting effects on cell proliferation and migration of miR-197-3p deletion was abrogated by either si-IGF1R or si-BCL2. CONCLUSION miR-197-3p modifies cell behaviors of proliferation, apoptosis and migration by targeting IGF1R and BCL2 in KD, providing a new perspective for the treatment of KD clinically.
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Affiliation(s)
- Yan Li
- Department of Pediatric Cardiology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China Chengdu 611731, China
| | - Xindan Wu
- Department of Pediatric Cardiology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China Chengdu 611731, China
| | - Fang Gao
- Department of Pediatric Cardiology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China Chengdu 611731, China
| | - Xianmin Wang
- Department of Pediatric Cardiology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China Chengdu 611731, China
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Ibrahim A, Chopra S. Succinate Dehydrogenase–Deficient Gastrointestinal Stromal Tumors. Arch Pathol Lab Med 2019; 144:655-660. [DOI: 10.5858/arpa.2018-0370-rs] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Succinate dehydrogenase (SDH)–deficient gastrointestinal stromal tumor (GIST) is a subset of wild-type GIST that constitutes approximately 10% of gastric GISTs. SDH-mutated GISTs lack mutations in the proto-oncogene receptor tyrosine kinase (also known as KIT, c-KIT, or CD117) or platelet-derived growth factor receptor α (PDGFR-α). These tumors have female predilection, affect children and young adults, and have a spectrum of behavior from indolent to progressive. These tumors have characteristic morphologic features including multinodular architecture, multiple tumors, lymphovascular involvement, and occasional lymph node metastasis. They can be seen in patients with Carney triad or Carney-Stratakis syndrome. Although a mutation in any one of the SDH subunits can be pathogenic, deficiency of a single subunit leads to loss of detectable SDH subunit B by immunohistochemistry, enabling a convenient, tissue-based screening method. The prognosis and the clinical course of these tumors is different from that of KIT- or PDGFR-α–mutated GISTs. Surgical management is considered the main line of treatment. SDH-mutated GISTs do not respond well to the common targeted therapy, with no objective tumor response to imatinib. The role of the pathologist in diagnosing these cases is imperative in management and subsequent follow-up.
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Affiliation(s)
- Ahmad Ibrahim
- From the Department of Pathology, LAC + USC Medical Center, University of Southern California, Keck School of Medicine, Los Angeles (Dr Ibrahim); and the Department of Pathology, University of Southern California, Keck School of Medicine, Los Angeles (Dr Chopra)
| | - Shefali Chopra
- From the Department of Pathology, LAC + USC Medical Center, University of Southern California, Keck School of Medicine, Los Angeles (Dr Ibrahim); and the Department of Pathology, University of Southern California, Keck School of Medicine, Los Angeles (Dr Chopra)
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Verschuur AC, Bajčiová V, Mascarenhas L, Khosravan R, Lin X, Ingrosso A, Janeway KA. Sunitinib in pediatric patients with advanced gastrointestinal stromal tumor: results from a phase I/II trial. Cancer Chemother Pharmacol 2019; 84:41-50. [PMID: 31006038 PMCID: PMC6561985 DOI: 10.1007/s00280-019-03814-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Accepted: 03/08/2019] [Indexed: 01/24/2023]
Abstract
BACKGROUND Sunitinib is approved for treatment of adults with imatinib-resistant gastrointestinal stromal tumor (GIST) or imatinib intolerance. METHODS This single-arm, multicenter, multinational phase I/II clinical trial (NCT01396148) enrolled eligible patients aged 6 to < 18 years with advanced, unresectable GIST with non-mutant KIT, or who demonstrated disease progression or intolerance to imatinib. Patients received sunitinib 15 mg/m2 per day, 4-weeks-on/2-weeks-off (schedule 4/2), for ≤ 18 cycles over 24 months. Intra-patient dose escalation to 22.5 and subsequently 30 mg/m2 were permitted based on individual patient tolerability and supported by real-time pharmacokinetics (PK). Primary objective was PK characterization. Secondary objectives included safety, antitumor activity and PK/pharmacodynamic relationships. RESULTS Six patients were enrolled with median (range) age of 14 (13-16) years. All six patients completed at least three treatment cycles, with one completing all 18 cycles. Five patients had a dose increase to 22.5 mg/m2; two of them had a further dose increase to 30 mg/m2. The average daily dose at cycle 3 was 21.1 mg/m2 (n = 6). Steady-state plasma concentrations were reached by day 15, cycle 1. No tumor responses were observed, but three patients had stabilization of the disease (50%). Median progression-free survival was 5.8 months (95% CI 2.3-not reached). There were no serious adverse events. CONCLUSIONS The tolerable dose of sunitinib in chemotherapy-naïve pediatric patients is at least 20 mg/m2 on schedule 4/2. The safety profile and PK of sunitinib in pediatric patients with GIST are comparable to those in adults.
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Affiliation(s)
- Arnauld C Verschuur
- Department of Pediatric Hematology and Oncology, Hôpital d'Enfants de la Timone, Assistance Publique-Hôpitaux de Marseille, 13005, Marseille, France.
| | - Viera Bajčiová
- University Hospital Brno-Children's Hospital, Brno, Czech Republic
| | - Leo Mascarenhas
- Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Pediatrics, Keck School of Medicine, Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA, USA
| | | | - Xun Lin
- Pfizer Inc, San Diego, CA, USA
| | | | - Katherine A Janeway
- Pediatrics, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA
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Moura DS, Ramos R, Fernandez-Serra A, Serrano T, Cruz J, Alvarez-Alegret R, Ortiz-Duran R, Vicioso L, Gomez-Dorronsoro ML, Garcia Del Muro X, Martinez-Trufero J, Rubio-Casadevall J, Sevilla I, Lainez N, Gutierrez A, Serrano C, Lopez-Alvarez M, Hindi N, Taron M, López-Guerrero JA, Martin-Broto J. Gene expression analyses determine two different subpopulations in KIT-negative GIST-like (KNGL) patients. Oncotarget 2018; 9:17576-17588. [PMID: 29707131 PMCID: PMC5915139 DOI: 10.18632/oncotarget.24799] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2017] [Accepted: 02/28/2018] [Indexed: 02/07/2023] Open
Abstract
Introduction There are limited findings available on KIT-negative GIST-like (KNGL) population. Also, KIT expression may be post-transcriptionally regulated by miRNA221 and miRNA222. Hence, the aim of this study is to characterize KNGL population, by differential gene expression, and to analyze miRNA221/222 expression and their prognostic value in KNGL patients. Methods KIT, PDGFRA, DOG1, IGF1R, MIR221 and MIR222 expression levels were determined by qRT-PCR. We also analyzed KIT and PDGFRA mutations, DOG1 expression, by immunohistochemistry, along with clinical and pathological data. Disease-free survival (DFS) and overall survival (OS) differences were calculated using Log-rank test. Results Hierarchical cluster analyses from gene expression data identified two groups: group I had KIT, DOG1 and PDGFRA overexpression and IGF1R underexpression and group II had overexpression of IGF1R and low expression of KIT, DOG1 and PDGFRA. Group II had a significant worse OS (p = 0.013) in all the series, and showed a tendency for worse OS (p = 0.11), when analyzed only the localized cases. MiRNA222 expression was significantly lower in a control subset of KIT-positive GIST (p < 0.001). OS was significantly worse in KNGL cases with higher expression of MIR221 (p = 0.028) or MIR222 (p = 0.014). Conclusions We identified two distinct KNGL subsets, with a different prognostic value. Increased levels of miRNA221/222, which are associated with worse OS, could explain the absence of KIT protein expression of most KNGL tumors.
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Affiliation(s)
- David S Moura
- Institute of Biomedicine of Sevilla (IBiS, HUVR, CSIC, University of Sevilla), Sevilla, Spain
| | - Rafael Ramos
- Pathology Department, Son Espases University Hospital, Palma, Illes Baleares, Spain
| | | | - Teresa Serrano
- Pathology Department, Bellvitge University Hospital, IDIBELL, Barcelona, Spain
| | - Julia Cruz
- Pathology Department, Valencian Oncologic Institute, Valencia, Spain
| | | | - Rosa Ortiz-Duran
- Pathology Department, Josep Trueta University Hospital, Girona, Spain
| | - Luis Vicioso
- Pathology Department, Virgen de la Victoria University Hospital, Malaga, Spain
| | | | - Xavier Garcia Del Muro
- Medical Oncology Department, Institut Català d'Oncologia, IDIBELL, Universitat de Barcelona, Barcelona, Spain
| | | | - Jordi Rubio-Casadevall
- Medical Oncology Department, Catalan Oncologic Institute, Josep Trueta University Hospital, Girona, Spain
| | - Isabel Sevilla
- Medical Oncology Department, Virgen de la Victoria University Hospital, Malaga, Spain
| | - Nuria Lainez
- Medical Oncology Department, Hospital Complex of Navarra, Pamplona, Spain
| | - Antonio Gutierrez
- Hematology Department, Son Espases University Hospital, Palma, Illes Baleares, Spain
| | - Cesar Serrano
- Medical Oncology Department, Vall d'Hebron Institute of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Maria Lopez-Alvarez
- Institute of Biomedicine of Sevilla (IBiS, HUVR, CSIC, University of Sevilla), Sevilla, Spain
| | - Nadia Hindi
- Institute of Biomedicine of Sevilla (IBiS, HUVR, CSIC, University of Sevilla), Sevilla, Spain.,Medical Oncology Department, University Hospital Virgen del Rocio, Sevilla, Spain
| | - Miguel Taron
- Institute of Biomedicine of Sevilla (IBiS, HUVR, CSIC, University of Sevilla), Sevilla, Spain
| | | | - Javier Martin-Broto
- Institute of Biomedicine of Sevilla (IBiS, HUVR, CSIC, University of Sevilla), Sevilla, Spain.,Medical Oncology Department, University Hospital Virgen del Rocio, Sevilla, Spain
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Wozniak A, Gebreyohannes YK, Debiec-Rychter M, Schöffski P. New targets and therapies for gastrointestinal stromal tumors. Expert Rev Anticancer Ther 2017; 17:1117-1129. [PMID: 29110548 DOI: 10.1080/14737140.2017.1400386] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION The majority of gastrointestinal stromal tumors (GIST) are driven by an abnormal receptor tyrosine kinase (RTK) signaling, occurring mainly due to somatic mutations in KIT or platelet derived growth factor receptor alpha (PDGFRA). Although the introduction of tyrosine kinase inhibitors (TKIs) has revolutionized therapy for GIST patients, with time the vast majority of them develop TKI resistance. Advances in understanding the molecular background of GIST resistance allows for the identification of new targets and the development of novel strategies to overcome or delay its occurrence. Areas covered: The focus of this review is on novel, promising therapeutic approaches to overcome heterogeneous resistance to registered TKIs. These approaches involve new TKIs, including drugs specific for a mutated form of KIT/PDGFRA, drugs with inhibitory effect against multiple RTKs, compounds targeting dysregulated downstream signaling pathways, drugs affecting KIT expression and degradation, inhibitors of cell cycle, and immunotherapeutics. Expert commentary: As the resistance to standard TKI treatment can be heterogeneous, a combinational approach for refractory GIST could be beneficial. Moreover, the understanding of the molecular background of resistant disease would allow development of a more personalized approach for these patients and their response to targeted therapy could be monitored closely using 'liquid biopsy'.
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Affiliation(s)
- Agnieszka Wozniak
- a Laboratory of Experimental Oncology, Department of Oncology , KU Leuven , Leuven , Belgium
| | | | | | - Patrick Schöffski
- a Laboratory of Experimental Oncology, Department of Oncology , KU Leuven , Leuven , Belgium.,c Department of General Medical Oncology , University Hospitals Leuven, Leuven Cancer Institute , Leuven , Belgium
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10
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Dual Targeting of Insulin Receptor and KIT in Imatinib-Resistant Gastrointestinal Stromal Tumors. Cancer Res 2017; 77:5107-5117. [DOI: 10.1158/0008-5472.can-17-0917] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Revised: 06/22/2017] [Accepted: 07/21/2017] [Indexed: 11/16/2022]
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11
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Pantaleo MA, Ravegnini G, Astolfi A, Simeon V, Nannini M, Saponara M, Urbini M, Gatto L, Indio V, Sammarini G, Santini D, Ferracin M, Negrini M, Hrelia P, Biasco G, Angelini S. Integrating miRNA and gene expression profiling analysis revealed regulatory networks in gastrointestinal stromal tumors. Epigenomics 2016; 8:1347-1366. [PMID: 27625077 DOI: 10.2217/epi-2016-0030] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
AIM Currently, little is known about differences in miRNA expression between KIT/PDGFRA mutant and KIT/PDGFRA wild-type (WT)-SDH deficient gastrointestinal stromal tumors (GIST). This prompted us to perform an integrated multiple expression profile of miRNA and mRNA, constructing an original miRNA-mRNA regulatory network in KIT/PDGFRA WT-SDH deficient GIST patients. PATIENTS & METHODS Analyses were carried out on KIT/PDGFRA mutant versus KIT/PDGFRA WT-SDH deficient GIST. Genome-wide miRNA and gene-expression analysis were performed using Agilent Human miRNA microarray and Affimetrix array, respectively. RESULTS Three potential regulatory networks (IGF1R → miR-139-5p/miR-455/let-7b, cyclin-dependent kinase 6 (CDK6) → miR-139-5p/let-7b and CD44 → miR-330-3p) were identified. CONCLUSION The miR-139-5p, 455-5p and let-7b signature, in particular, may represent an important therapeutic target in KIT/PDGFRA WT-SDH deficient GIST, usually characterized by IGF1R overexpression.
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Affiliation(s)
- Maria Abbondanza Pantaleo
- 'Giorgio Prodi' Cancer Research Center, University of Bologna, Bologna, Italy.,Department of Specialized, Experimental & Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Gloria Ravegnini
- Department of Pharmacy & Biotechnology, Via Irnerio 48, 40126 Bologna, Italy
| | - Annalisa Astolfi
- 'Giorgio Prodi' Cancer Research Center, University of Bologna, Bologna, Italy
| | - Vittorio Simeon
- Laboratory of Pre-Clinical & Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture (PZ), Italy
| | - Margherita Nannini
- Department of Specialized, Experimental & Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Maristella Saponara
- Department of Specialized, Experimental & Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Milena Urbini
- Department of Specialized, Experimental & Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Lidia Gatto
- Department of Specialized, Experimental & Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Valentina Indio
- Department of Specialized, Experimental & Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Giulia Sammarini
- Department of Pharmacy & Biotechnology, Via Irnerio 48, 40126 Bologna, Italy
| | - Donatella Santini
- Pathology Unit, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Manuela Ferracin
- Department of Specialized, Experimental & Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Massimo Negrini
- Department of Morphology, Surgery & Experimental Medicine, University of Ferrara, Ferrara, Italy
| | - Patrizia Hrelia
- Department of Pharmacy & Biotechnology, Via Irnerio 48, 40126 Bologna, Italy
| | - Guido Biasco
- 'Giorgio Prodi' Cancer Research Center, University of Bologna, Bologna, Italy.,Department of Specialized, Experimental & Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
| | - Sabrina Angelini
- Department of Pharmacy & Biotechnology, Via Irnerio 48, 40126 Bologna, Italy
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12
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Nannini M, Ravegnini G, Angelini S, Astolfi A, Biasco G, Pantaleo MA. miRNA profiling in gastrointestinal stromal tumors: implication as diagnostic and prognostic markers. Epigenomics 2015; 7:1033-49. [PMID: 26447534 DOI: 10.2217/epi.15.52] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
MicroRNAs are a class of short noncoding RNAs, that play a relevant role in multiple biological processes, such as differentiation, proliferation and apoptosis. Gastrointestinal stromal tumors (GIST) are considered as a paradigm of molecular biology in solid tumors worldwide, and after the discovery of specific alterations in the KIT and PDGFRA genes, they have emerged from anonymity to become a model for targeted therapy. Epigenetics have an emerging and relevant role in different steps of GIST biology such as tumorigenesis, disease progression, prognosis and drug resistance. The aim of the present review was to summarize the current evidence about the role of microRNAs in GIST, including their potential application as well as their limits.
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Affiliation(s)
- Margherita Nannini
- Department of Specialized, Experimental & Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Gloria Ravegnini
- Department of Pharmacy & Biotechnology, FaBit; University of Bologna, Italy
| | - Sabrina Angelini
- Department of Pharmacy & Biotechnology, FaBit; University of Bologna, Italy
| | - Annalisa Astolfi
- "Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna, Italy
| | - Guido Biasco
- Department of Specialized, Experimental & Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.,"Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna, Italy
| | - Maria A Pantaleo
- Department of Specialized, Experimental & Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.,"Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna, Italy
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13
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Expression of CD117, DOG-1, and IGF-1R in gastrointestinal stromal tumours - an analysis of 70 cases from 2004 to 2010. GASTROENTEROLOGY REVIEW 2015; 11:115-22. [PMID: 27350839 PMCID: PMC4916232 DOI: 10.5114/pg.2015.52587] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Accepted: 03/08/2015] [Indexed: 12/12/2022]
Abstract
Introduction Determination of the type of mutations in gastrointestinal stromal tumours (GIST) plays a major role in assessing the risk of progression of the disease, and also allows determination of the clinical management and treatment. More accurate GIST diagnosis is possible by using simultaneously various types of antibodies to immunohistochemistry methods in routine procedures. Aim To evaluate the expression of CD117, DOG-1, and IGF-1R in patients with gastrointestinal stromal tumours, and analysis of the impact of the examined protein expression on patient survival with emphasis on specific recognition and prognostication of these tumours. Material and methods The protein expression was analyzed in 70 patients who had undergone surgical treatment for mesenchymal tumours of the gastrointestinal tract, using the immunohistochemical method. Results Positive expression of CD117, DOG-1, and IGF1R included 95.71%, 88.57% and 11.43% of study GISTs, respectively. Statistical analysis showed positive significant correlation between DOG-1 expression and histological type of tumour (p = 0.024). Analysis of overall survival curves of 70 GIST patients according to expression of CD117, DOG-1, and IGF1R did not show a tendency towards longer survival of patients with positive expression (p > 0.05). Conclusions Predictive factors determining the survival time of patients are strongly associated with morphological features of tumours. A thorough analysis of each case plays a key role in predicting survival time of patients and may be a clue in targeting the therapeutic procedure.
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Ordog T, Zörnig M, Hayashi Y. Targeting Disease Persistence in Gastrointestinal Stromal Tumors. Stem Cells Transl Med 2015; 4:702-7. [PMID: 25934947 DOI: 10.5966/sctm.2014-0298] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2014] [Accepted: 03/16/2015] [Indexed: 01/11/2023] Open
Abstract
UNLABELLED SummaryGastrointestinal stromal tumors (GISTs) represent 20%-40% of human sarcomas. Although approximately half of GISTs are cured by surgery, prognosis of advanced disease used to be poor due to the high resistance of these tumors to conventional chemo- and radiotherapy. The introduction of molecularly targeted therapy (e.g., with imatinib mesylate) following the discovery of the role of oncogenic mutations in the receptor tyrosine kinases KIT and platelet-derived growth factor α (PDGFRA) significantly increased patient survival. However, GIST cells persist in 95%-97% of imatinib-treated patients who eventually progress and die of the disease because of the emergence of clones with drug-resistant mutations. Because these secondary mutations are highly heterogeneous, even second- and third-line drugs that are effective against certain genotypes have only moderately increased progression-free survival. Consequently, alternative strategies such as targeting molecular mechanisms underlying disease persistence should be considered. We reviewed recently discovered cell-autonomous and microenvironmental mechanisms that could promote the survival of GIST cells in the presence of tyrosine kinase inhibitor therapy. We particularly focused on the potential role of adult precursors for interstitial cells of Cajal (ICCs), the normal counterpart of GISTs. ICC precursors share phenotypic characteristics with cells that emerge in a subset of patients treated with imatinib and in young patients with GIST characterized by loss of succinate dehydrogenase complex proteins and lack of KIT or PDGFRA mutations. Eradication of residual GIST cells and cure of GIST will likely require individualized combinations of several approaches tailored to tumor genotype and phenotype. SIGNIFICANCE Gastrointestinal stromal tumors (GISTs) are one of the most common connective tissue cancers. Most GISTs that cannot be cured by surgery respond to molecularly targeted therapy (e.g., with imatinib); however, tumor cells persist in almost all patients and eventually acquire drug-resistant mutations. Several mechanisms contribute to the survival of GIST cells in the presence of imatinib, including the activation of "escape" mechanisms and the selection of stem-like cells that are not dependent on the expression of the drug targets for survival. Eradication of residual GIST cells and cure of GIST will likely require individualized combinations of several approaches tailored to the genetic makeup and other characteristics of the tumors.
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Affiliation(s)
- Tamas Ordog
- Center for Individualized Medicine, Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, and Enteric Neuroscience Program, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA;
| | - Martin Zörnig
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Frankfurt, Germany
| | - Yujiro Hayashi
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, and Enteric Neuroscience Program, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA
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15
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Zhu JQ, Ou WB. Therapeutic targets in gastrointestinal stromal tumors. World J Transl Med 2015; 4:25-37. [DOI: 10.5528/wjtm.v4.i1.25] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2014] [Revised: 09/14/2014] [Accepted: 12/01/2014] [Indexed: 02/05/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common type of mesenchymal tumor of the gastrointestinal tract. The tumorigenesis of GISTs is driven by gain-of-function mutations in KIT or platelet-derived growth factor receptor α (PDGFRA), resulting in constitutive activation of the tyrosine kinase and its downstream signaling pathways. Oncogenic KIT or PDGFRA mutations are compelling therapeutic targets for the treatment of GISTs, and the KIT/PDGFRA inhibitor imatinib is the standard of care for patients with metastatic GISTs. However, most GIST patients develop clinical resistance to imatinib and other tyrosine kinase inhibitors. Five mechanisms of resistance have been characterized: (1) acquisition of a secondary point mutation in KIT or PDGFRA; (2) genomic amplification of KIT; (3) activation of an alternative receptor tyrosine kinase; (4) loss of KIT oncoprotein expression; and (5) wild-type GIST. Currently, sunitinib is used as a second-line treatment for patients after imatinib failure, and regorafenib has been approved for patients whose disease is progressing on both imatinib and sunitinib. Phase II/III trials are currently in progress to evaluate novel inhibitors and immunotherapies targeting KIT, its downstream effectors such as phosphatidylinositol 3-kinase, protein kinase B and mammalian target of rapamycin, heat shock protein 90, and histone deacetylase inhibitor. Other candidate targets have been identified, including ETV1, AXL, insulin-like growth factor 1 receptor, KRAS, FAS receptor, protein kinase c theta, ANO1 (DOG1), CDC37, and aurora kinase A. These candidates warrant clinical evaluation as novel therapeutic targets in GIST.
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16
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Wang YM, Gu ML, Ji F. Succinate dehydrogenase-deficient gastrointestinal stromal tumors. World J Gastroenterol 2015; 21:2303-2314. [PMID: 25741136 PMCID: PMC4342905 DOI: 10.3748/wjg.v21.i8.2303] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Revised: 09/22/2014] [Accepted: 12/16/2014] [Indexed: 02/07/2023] Open
Abstract
Most gastrointestinal stromal tumors (GISTs) are characterized by KIT or platelet-derived growth factor alpha (PDGFRA) activating mutations. However, there are still 10%-15% of GISTs lacking KIT and PDGFRA mutations, called wild-type GISTs (WT GISTs). Among these so-called WT GISTs, a small subset is associated with succinate dehydrogenase (SDH) deficiency, known as SDH-deficient GISTs. In addition, GISTs that occur in Carney triad and Carney-Stratakis syndrome represent specific examples of SDH-deficient GISTs. SDH-deficient GISTs locate exclusively in the stomach, showing predilection for children and young adults with female preponderance. The tumor generally pursues an indolent course and exhibits primary resistance to imatinib therapy in most cases. Loss of succinate dehydrogenase subunit B expression and overexpression of insulin-like growth factor 1 receptor (IGF1R) are common features of SDH-deficient GISTs. In WT GISTs without succinate dehydrogenase activity, upregulation of hypoxia-inducible factor 1α may lead to increased growth signaling through IGF1R and vascular endothelial growth factor receptor (VEGFR). As a result, IGF1R and VEGFR are promising to be the novel therapeutic targets of GISTs. This review will update the current knowledge on characteristics of SDH-deficient GISTs and further discuss the possible mechanisms of tumorigenesis and clinical management of SDH-deficient GISTs.
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17
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Boikos SA, Stratakis CA. The genetic landscape of gastrointestinal stromal tumor lacking KIT and PDGFRA mutations. Endocrine 2014; 47:401-8. [PMID: 25027296 PMCID: PMC4729312 DOI: 10.1007/s12020-014-0346-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Accepted: 06/24/2014] [Indexed: 12/17/2022]
Abstract
About 10-15 % of adult gastrointestinal stromal tumors (GISTs) and 85 % of pediatric GISTs do not have mutations in the KIT or PDGFRA genes and are generally classified as KIT/PDGFRA wild type (WT). Recent studies have shown that this group of KIT/PDGFRA WT GISTs is quite heterogeneous in terms of clinical phenotype, genetic etiology, and molecular pathways. Succinate dehydrogenase subunit (SDH)-deficient GISTs, which include tumors that are part of multiple endocrine neoplasia syndromes, are the newest group of KIT/PDGFRA WT GIST to be molecularly elucidated. This review aims to describe the different genetic subgroups of KIT/PDGFRA WT GIST, with a special focus on the SDH-deficient GIST.
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Affiliation(s)
- Sosipatros A Boikos
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA,
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18
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He M, Crow J, Roth M, Zeng Y, Godwin AK. Integrated immunoisolation and protein analysis of circulating exosomes using microfluidic technology. LAB ON A CHIP 2014; 14:3773-80. [PMID: 25099143 PMCID: PMC4161194 DOI: 10.1039/c4lc00662c] [Citation(s) in RCA: 355] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Accepted: 07/18/2014] [Indexed: 05/02/2023]
Abstract
Developing blood-based tests is appealing for non-invasive disease diagnosis, especially when biopsy is difficult, costly, and sometimes not even an option. Tumor-derived exosomes have attracted increasing interest in non-invasive cancer diagnosis and monitoring of treatment response. However, the biology and clinical value of exosomes remains largely unknown due in part to current technical challenges in rapid isolation, molecular classification and comprehensive analysis of exosomes. Here we developed a new microfluidic approach to streamline and expedite the exosome analysis pipeline by integrating specific immunoisolation and targeted protein analysis of circulating exosomes. Compared to the conventional methods, our approach enables selective subpopulation isolation and quantitative detection of surface and intravesicular biomarkers directly from a minimally invasive amount of plasma samples (30 μL) within ~100 min with markedly improved detection sensitivity. Using this device, we demonstrated phenotyping of exosome subpopulations by targeting a panel of common exosomal and tumor-specific markers and multiparameter analyses of intravesicular biomarkers in the selected subpopulation. We were able to assess the total expression and phosphorylation levels of IGF-1R in non-small-cell lung cancer patients by probing plasma exosomes as a non-invasive alternative to conventional tissue biopsy. We foresee that the microfluidic exosome analysis platform will form the basis for critically needed infrastructures for advancing the biology and clinical utilization of exosomes.
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Affiliation(s)
- Mei He
- Department of Pathology and Laboratory Medicine , University of Kansas Medical Center , Kansas City , KS 66160 , USA . ; Fax: +1 (913) 945 6373 ; Tel: +1 (913) 945 6327
| | - Jennifer Crow
- Department of Pathology and Laboratory Medicine , University of Kansas Medical Center , Kansas City , KS 66160 , USA . ; Fax: +1 (913) 945 6373 ; Tel: +1 (913) 945 6327
| | - Marc Roth
- Department of Pathology and Laboratory Medicine , University of Kansas Medical Center , Kansas City , KS 66160 , USA . ; Fax: +1 (913) 945 6373 ; Tel: +1 (913) 945 6327
| | - Yong Zeng
- Department of Chemistry , Ralph N Adams Institute for Bioanalytical Chemistry , and Bioengineering Graduate Program , University of Kansas , Lawrence , KS 66045 , USA . ; Fax: +1 (785) 864 5396 ; Tel: +1 (785) 864 8105
| | - Andrew K. Godwin
- Department of Pathology and Laboratory Medicine , University of Kansas Medical Center , Kansas City , KS 66160 , USA . ; Fax: +1 (913) 945 6373 ; Tel: +1 (913) 945 6327
- University of Kansas Cancer Center , Kansas City , KS 66160 , USA
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Miettinen M, Lasota J. Succinate dehydrogenase deficient gastrointestinal stromal tumors (GISTs) - a review. Int J Biochem Cell Biol 2014; 53:514-9. [PMID: 24886695 DOI: 10.1016/j.biocel.2014.05.033] [Citation(s) in RCA: 106] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2014] [Revised: 05/20/2014] [Accepted: 05/21/2014] [Indexed: 02/07/2023]
Abstract
Loss of function of the succinate dehydrogenase complex characterizes a rare group of human tumors including some gastrointestinal stromal tumors, paragangliomas, renal carcinomas, and pituitary adenomas, and these can all be characterized as SDH-deficient tumors. Approximately 7.5% of gastric gastrointestinal stromal tumors are SDH-deficient and not driven by KIT/PDGFRA mutations, as are most other GISTs. The occurrence of SDH-deficient GISTs is restricted to stomach, and they typically occur in children and young adults representing a spectrum of clinical behavior from indolent to progressive. Slow progression is a common feature even after metastatic spread has taken place, and many patients live years with metastases. SDH-deficient GISTs have characteristic morphologic features including multinodular gastric wall involvement, often multiple separate tumors, common lymphovascular invasion, and occasional lymph node metastases. Diagnostic is the loss of succinate dehydrogenase subunit B (SDHB) from the tumor cells and this can be practically assessed by immunohistochemistry. SDHA is lost in cases associated with SDHA mutations. Approximately half of the patients have SDH subunit gene mutations, often germline and most commonly A (30%), and B, C or D (together 20%), with both alleles inactivated in the tumor cells according to the classic tumor suppressor gene model. Half of the cases are not associated with SDH-mutations and epigenetic silencing of the SDH complex is the possible pathogenesis. Extensive genomic methylation has been observed in these tumors, which is in contrast with other GISTs. SDH-loss causes succinate accumulation and activation of pseudohypoxia signaling via overexpression of HIF-proteins. Activation of insulin-like growth factor 1-signaling is also typical of these tumors. SDH-deficient GISTs are a unique group of GISTs with an energy metabolism defect as the key oncogenic mechanism. This article is part of a Directed Issue entitled: Rare Cancers.
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Affiliation(s)
- Markku Miettinen
- Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA.
| | - Jerzy Lasota
- Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA
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20
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Doyle LA, Hornick JL. Gastrointestinal stromal tumours: from KIT to succinate dehydrogenase. Histopathology 2013; 64:53-67. [DOI: 10.1111/his.12302] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Leona A Doyle
- Department of Pathology; Brigham and Women's Hospital ; Harvard Medical School; Boston MA USA
| | - Jason L Hornick
- Department of Pathology; Brigham and Women's Hospital ; Harvard Medical School; Boston MA USA
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21
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Hayashi Y, Asuzu DT, Gibbons SJ, Aarsvold KH, Bardsley MR, Lomberk GA, Mathison AJ, Kendrick ML, Shen KR, Taguchi T, Gupta A, Rubin BP, Fletcher JA, Farrugia G, Urrutia RA, Ordog T. Membrane-to-nucleus signaling links insulin-like growth factor-1- and stem cell factor-activated pathways. PLoS One 2013; 8:e76822. [PMID: 24116170 PMCID: PMC3792098 DOI: 10.1371/journal.pone.0076822] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2013] [Accepted: 08/29/2013] [Indexed: 11/29/2022] Open
Abstract
Stem cell factor (mouse: Kitl, human: KITLG) and insulin-like growth factor-1 (IGF1), acting via KIT and IGF1 receptor (IGF1R), respectively, are critical for the development and integrity of several tissues. Autocrine/paracrine KITLG-KIT and IGF1-IGF1R signaling are also activated in several cancers including gastrointestinal stromal tumors (GIST), the most common sarcoma. In murine gastric muscles, IGF1 promotes Kitl-dependent development of interstitial cells of Cajal (ICC), the non-neoplastic counterpart of GIST, suggesting cooperation between these pathways. Here, we report a novel mechanism linking IGF1-IGF1R and KITLG-KIT signaling in both normal and neoplastic cells. In murine gastric muscles, the microenvironment for ICC and GIST, human hepatic stellate cells (LX-2), a model for cancer niches, and GIST cells, IGF1 stimulated Kitl/KITLG protein and mRNA expression and promoter activity by activating several signaling pathways including AKT-mediated glycogen synthase kinase-3β inhibition (GSK3i). GSK3i alone also stimulated Kitl/KITLG expression without activating mitogenic pathways. Both IGF1 and GSK3i induced chromatin-level changes favoring transcriptional activation at the Kitl promoter including increased histone H3/H4 acetylation and H3 lysine (K) 4 methylation, reduced H3K9 and H3K27 methylation and reduced occupancy by the H3K27 methyltransferase EZH2. By pharmacological or RNA interference-mediated inhibition of chromatin modifiers we demonstrated that these changes have the predicted impact on KITLG expression. KITLG knock-down and immunoneutralization inhibited the proliferation of GIST cells expressing wild-type KIT, signifying oncogenic autocrine/paracrine KITLG-KIT signaling. We conclude that membrane-to-nucleus signaling involving GSK3i establishes a previously unrecognized link between the IGF1-IGF1R and KITLG-KIT pathways, which is active in both physiologic and oncogenic contexts and can be exploited for therapeutic purposes.
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Affiliation(s)
- Yujiro Hayashi
- Enteric Neuroscience Program, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, United States of America
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States of America
| | - David T. Asuzu
- Enteric Neuroscience Program, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, United States of America
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States of America
| | - Simon J. Gibbons
- Enteric Neuroscience Program, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, United States of America
| | - Kirsten H. Aarsvold
- Enteric Neuroscience Program, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, United States of America
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States of America
| | - Michael R. Bardsley
- Enteric Neuroscience Program, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, United States of America
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States of America
| | - Gwen A. Lomberk
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States of America
| | - Angela J. Mathison
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States of America
| | - Michael L. Kendrick
- Department of Surgery, Mayo Clinic, Rochester, Minnesota, United States of America
| | - K. Robert Shen
- Department of Surgery, Mayo Clinic, Rochester, Minnesota, United States of America
| | - Takahiro Taguchi
- Division of Human Health and Medical Science, Graduate School of Kuroshio Science, Kochi University, Nankoku, Kochi, Japan
| | - Anu Gupta
- Departments of Anatomic Pathology and Molecular Genetics, Lerner Research Institute and Taussig Cancer Center, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Brian P. Rubin
- Departments of Anatomic Pathology and Molecular Genetics, Lerner Research Institute and Taussig Cancer Center, Cleveland Clinic, Cleveland, Ohio, United States of America
| | - Jonathan A. Fletcher
- Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
| | - Gianrico Farrugia
- Enteric Neuroscience Program, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, United States of America
- Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America
| | - Raul A. Urrutia
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States of America
- Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America
| | - Tamas Ordog
- Enteric Neuroscience Program, Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, United States of America
- Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, United States of America
- Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America
- * E-mail:
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Rajendra R, Pollack SM, Jones RL. Management of gastrointestinal stromal tumors. Future Oncol 2013; 9:193-206. [PMID: 23414470 DOI: 10.2217/fon.12.178] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) comprise <1% of all gastrointestinal tumors, but are the most common mesenchymal tumors of the GI tract. This review highlights the dramatic changes in clinical practice with regards to GIST in the last decade, with a focus on overall management and recent developments. For localized primary GISTs, surgical resection is the mainstay of therapy with the 5-year survival rate after complete resection averaging approximately 50-65%. Factors such as tumor size, mitotic rate, tumor location, kinase mutational status and occurrence of tumor rupture have been extensively studied and proposed to be predictors of outcome. Adjuvant imatinib is proposed as an option for those patients with a substantial risk of relapse. Unresectable metastatic or recurrent GIST can be treated with imatinib, with a remarkable response rate (50-70%) and prolonged survival (median progression-free survival: 18-20 months; median overall survival: 51-57 months). Sunitinib is licensed as a second-line therapy following progression on imatinib. Other promising systemic therapies include regorafenib and agents targeting the PI3K/mTOR pathway.
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Affiliation(s)
- Rajeev Rajendra
- University of Washington/Fred Hutchinson Cancer Research Center, 825 Eastlake Avenue E., G3630, Seattle, WA 98109-1023, USA
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23
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Nannini M, Biasco G, Astolfi A, Pantaleo MA. An overview on molecular biology of KIT/PDGFRA wild type (WT) gastrointestinal stromal tumours (GIST). J Med Genet 2013; 50:653-61. [DOI: 10.1136/jmedgenet-2013-101695] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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24
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Nannini M, Astolfi A, Paterini P, Urbini M, Santini D, Catena F, Indio V, Casadio R, Pinna AD, Biasco G, Pantaleo MA. Expression of IGF-1 receptor in KIT/PDGF receptor-α wild-type gastrointestinal stromal tumors with succinate dehydrogenase complex dysfunction. Future Oncol 2013; 9:121-6. [PMID: 23252569 DOI: 10.2217/fon.12.170] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
KIT/PDGF receptor-α (PDGFRA) wild-type (WT) gastrointestinal stromal tumors (GIST) are characterized by an overexpression of IGF-1 receptor (IGF1R) at the mRNA and protein level. More recently, germline and somatic mutations in succinate dehydrogenase (SDH) subunits A, B and C have been identified in KIT/PDGFRA WT sporadic GIST. Until now, the molecular basis of IGF1R overexpression in KIT/PDGFRA WT GIST has not been explained. In this brief report we investigate the status of the SDH complex at the genomic and protein level in relation to IGF1R expression at the mRNA and protein level in seven KIT/PDGFRA WT sporadic GIST patients. We found that IGF1R was upregulated in all patients harboring SDH mutations or displaying a SDH dysfunction, with respect to KIT/PDGFRA WT GIST without SDH mutations. Western blot analysis confirmed that all patients with an upregulation of IGF1R mRNA had detectable IGF1R protein expression. This report would suggest that IGF1R overexpression in KIT/PDGFRA WT GIST could be driven by the loss-of-function of the SDH mitochondrial complex.
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Affiliation(s)
- Margherita Nannini
- Department of Hematology & Oncological Sciences L&A Seràgnoli, S. Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138, Bologna, Italy.
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Kelly L, Bryan K, Kim SY, Janeway KA, Killian JK, Schildhaus HU, Miettinen M, Helman L, Meltzer PS, van de Rijn M, Debiec-Rychter M, O’Sullivan M. Post-transcriptional dysregulation by miRNAs is implicated in the pathogenesis of gastrointestinal stromal tumor [GIST]. PLoS One 2013; 8:e64102. [PMID: 23717541 PMCID: PMC3663836 DOI: 10.1371/journal.pone.0064102] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Accepted: 04/09/2013] [Indexed: 12/12/2022] Open
Abstract
In contrast to adult mutant gastrointestinal stromal tumors [GISTs], pediatric/wild-type GISTs remain poorly understood overall, given their lack of oncogenic activating tyrosine kinase mutations. These GISTs, with a predilection for gastric origin in female patients, show limited response to therapy with tyrosine kinase inhibitors and generally pursue a more indolent course, but still may prove fatal. Defective cellular respiration appears to underpin tumor development in these wild-type cases, which as a group lack expression of succinate dehydrogenase [SDH] B, a surrogate marker for respiratory chain metabolism. Yet, only a small subset of the wild-type tumors show mutations in the genes coding for the SDH subunits [SDHx]. To explore additional pathogenetic mechanisms in these wild-type GISTs, we elected to investigate post-transcriptional regulation of these tumors by conducting microRNA (miRNA) profiling of a mixed cohort of 73 cases including 18 gastric pediatric wild-type, 25 (20 gastric, 4 small bowel and 1 retroperitoneal) adult wild-type GISTs and 30 gastric adult mutant GISTs. By this approach we have identified distinct signatures for GIST subtypes which correlate tightly with clinico-pathological parameters. A cluster of miRNAs on 14q32 show strikingly different expression patterns amongst GISTs, a finding which appears to be explained at least in part by differential allelic methylation of this imprinted region. Small bowel and retroperitoneal wild-type GISTs segregate with adult mutant GISTs and express SDHB, while adult wild-type gastric GISTs are dispersed amongst adult mutant and pediatric wild-type cases, clustering in this situation on the basis of SDHB expression. Interestingly, global methylation analysis has recently similarly demonstrated that these wild-type, SDHB-immunonegative tumors show a distinct pattern compared with KIT and PDGFRA mutant tumors, which as a rule do express SDHB. All cases with Carney triad within our cohort cluster together tightly.
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Affiliation(s)
- Lorna Kelly
- Histopathology Department, School of Medicine, Trinity College Dublin, Dublin, Ireland
- National Children’s Research Centre, Our Lady’s Children’s Hospital, Crumlin, Dublin, Ireland
| | - Kenneth Bryan
- Computational Biology, Systems Biology/Immunology, Animal and Grassland Research and Innovation Centre, Teagasc, Dunsany, County Meath, Ireland
| | - Su Young Kim
- Centre for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America
| | - Katherine A. Janeway
- Department of Pediatric Hematology-Oncology, Dana Farber Cancer Institute and Children’s Hospital, Boston, Massachusetts, United States of America
| | - J. Keith Killian
- Centre for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America
| | | | - Markku Miettinen
- Centre for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America
| | - Lee Helman
- Centre for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America
| | - Paul S. Meltzer
- Centre for Cancer Research, National Cancer Institute, Bethesda, Maryland, United States of America
| | - Matt van de Rijn
- Department of Pathology, Stanford University Medical Centre, Stanford, California, United States of America
| | - Maria Debiec-Rychter
- Department of Human Genetics, Catholic University Leuven and University Hospitals, Leuven, Belgium
| | - Maureen O’Sullivan
- Histopathology Department, School of Medicine, Trinity College Dublin, Dublin, Ireland
- National Children’s Research Centre, Our Lady’s Children’s Hospital, Crumlin, Dublin, Ireland
- * E-mail:
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26
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Belinsky MG, Rink L, von Mehren M. Succinate dehydrogenase deficiency in pediatric and adult gastrointestinal stromal tumors. Front Oncol 2013; 3:117. [PMID: 23730622 PMCID: PMC3656383 DOI: 10.3389/fonc.2013.00117] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2013] [Accepted: 04/26/2013] [Indexed: 12/18/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) in adults are generally driven by somatic gain-of-function mutations in KIT or PDGFRA, and biological therapies targeted to these receptor tyrosine kinases comprise part of the treatment regimen for metastatic and inoperable GISTs. A minority (10-15%) of GISTs in adults, along with ∼85% of pediatric GISTs, lacks oncogenic mutations in KIT and PDGFRA. Not surprisingly these wild type (WT) GISTs respond poorly to kinase inhibitor therapy. A subset of WT GISTs shares a set of distinguishing clinical and pathological features, and a flurry of recent reports has convincingly demonstrated shared molecular characteristics. These GISTs have a distinct transcriptional profile including over-expression of the insulin-like growth factor-1 receptor, and exhibit deficiency in the succinate dehydrogenase (SDH) enzyme complex. The latter is often but not always linked to bi-allelic inactivation of SDH subunit genes, particularly SDHA. This review will summarize the molecular, pathological, and clinical connections that link this group of SDH-deficient neoplasms, and offer a view toward understanding the underlying biology of the disease and the therapeutic challenges implicit to this biology.
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Affiliation(s)
- Martin G. Belinsky
- Department of Medical Oncology, Fox Chase Cancer CenterPhiladelphia, PA, USA
| | - Lori Rink
- Department of Medical Oncology, Fox Chase Cancer CenterPhiladelphia, PA, USA
| | - Margaret von Mehren
- Department of Medical Oncology, Fox Chase Cancer CenterPhiladelphia, PA, USA
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Shin HC, Bae YK, Gu MJ, Jung ES, Oh YH. Expression of insulin-like growth factor 1 and insulin-like growth factor 1 receptor is associated with the favorable clinicopathologic parameters in small intestinal carcinomas. Pathobiology 2013; 80:265-70. [PMID: 23689439 DOI: 10.1159/000350309] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Accepted: 02/27/2013] [Indexed: 11/19/2022] Open
Abstract
OBJECTIVE The insulin-like growth factor (IGF) system has been known to play a critical role in tumor development and progression in many human cancers. However, the role of the IGF system in small intestinal carcinoma (SIC) has not been studied yet. METHODS We evaluated the expression of IGF1 and IGF1 receptor (IFG1R) in a total of 194 cases of SIC. RESULTS IGF1 expression was associated with well/moderate differentiation, better survival, lower pT, lower stage and no lymph node metastasis. IGF1R was more diffusely and strongly expressed in tumors with lower pT and lower stage. CONCLUSIONS IGF1 and IGF1R expression is associated with favorable clinicopathologic parameters and may involve early carcinogenesis of SICs. Target therapy for the IGF1R signaling pathway may not have a major therapeutic role in treating SIC.
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Affiliation(s)
- Hyung Chan Shin
- Department of Pathology, Yeungnam University College of Medicine, Daegu 705-717, Korea
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28
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Wagner MJ, Maki RG. Type 1 insulin-like growth factor receptor targeted therapies in pediatric cancer. Front Oncol 2013; 3:9. [PMID: 23383402 PMCID: PMC3563098 DOI: 10.3389/fonc.2013.00009] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2012] [Accepted: 01/10/2013] [Indexed: 02/06/2023] Open
Abstract
Data from over 20 years ago demonstrated potential use for insulin-like growth factor (IGF) signaling modulators, specifically with IGF-1R antagonists, in a variety of pediatric and adolescent cancers, particularly in sarcomas. However, in spite of promising preclinical data, IGF-1R inhibitors have not had the success as single agents that was originally hoped for in clinical trials. Several potential mechanisms exist by which tumors are resistant to IGF-1R inhibitors. Notably, these resistance mechanisms are currently best understood in Ewing sarcoma and alveolar rhabdomyosarcoma. Various treatment schema have been proposed as a potential way to overcome this resistance. The use of IGF-1R inhibitors, mechanisms of resistance, and current ongoing clinical studies using IGF-1R inhibitors in pediatric cancers are reviewed here.
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Affiliation(s)
- Michael J Wagner
- Department of Medicine, Mount Sinai Medical Center New York, NY, USA
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Beadling C, Patterson J, Justusson E, Nelson D, Pantaleo MA, Hornick JL, Chacón M, Corless CL, Heinrich MC. Gene expression of the IGF pathway family distinguishes subsets of gastrointestinal stromal tumors wild type for KIT and PDGFRA. Cancer Med 2013; 2:21-31. [PMID: 24133624 PMCID: PMC3797556 DOI: 10.1002/cam4.57] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2012] [Revised: 11/19/2012] [Accepted: 12/13/2012] [Indexed: 12/25/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) arise from the interstitial cells of Cajal (ICCs) and are the most common mesenchymal neoplasm of the gastrointestinal tract. While the majority of GISTs harbor activating mutations in either the v-kit Hardy-Zuckerman feline sarcoma viral oncogene homolog (KIT) or platelet-derived growth factor receptor alpha (PDGFRA) tyrosine kinases, approximately 10–15% of adult GISTs and 85% of pediatric GISTs lack such mutations. These “wild-type” GISTs have been reported to express high levels of the insulin-like growth factor 1 receptor (IGF1R), and IGF1R-targeted therapy of wild-type GISTs is being evaluated in clinical trials. However, it is not clear that all wild-type GISTs express IGF1R, because studies to date have predominantly focused on a particular subtype of gastric wild-type GIST that is deficient in the mitochondrial succinate dehydrogenase (SDH) complex. This study of a series of 136 GISTs, including 72 wild-type specimens, was therefore undertaken to further characterize wild-type GIST subtypes based on the relative expression of transcripts encoding IGF1R. Additional transcripts relevant to GIST biology were also evaluated, including members of the IGF-signaling pathway (IGF1, IGF2, and insulin receptor [INSR]), neural markers (CDH2[CDH: Cadherin], neurofilament, light polypeptide, LHX2 [LHX: LIM homeobox], and KIRREL3 [KIRREL: kin of IRRE like]), KIT, PDGFRA, CD34, and HIF1A. Succinate dehydrogenase complex, subunit B protein expression was also assessed as a measure of SDH complex integrity. In addition to the previously described SDH-deficient, IGF1Rhigh wild-type GISTs, other SDH-intact wild-type subpopulations were defined by high relative expression of IGF1R, neural markers, IGF1 and INSR, or low IGF1R coupled with high IGF2. These results underscore the complexity and heterogeneity of wild-type GISTs that will need to be factored into molecularly-targeted therapeutic strategies.
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Affiliation(s)
- Carol Beadling
- Knight Cancer Institute, Oregon Health and Science University Portland, Oregon ; Division of Hematology and Oncology, Oregon Health and Science University Portland, Oregon
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Lasota J, Wang Z, Kim SY, Helman L, Miettinen M. Expression of the receptor for type i insulin-like growth factor (IGF1R) in gastrointestinal stromal tumors: an immunohistochemical study of 1078 cases with diagnostic and therapeutic implications. Am J Surg Pathol 2013; 37:114-9. [PMID: 22892600 PMCID: PMC3502638 DOI: 10.1097/pas.0b013e3182613c86] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
A majority of gastrointestinal stromal tumors (GISTs) carry gain-of-function KIT or platelet-derived growth factor receptor α (PDGFRA) mutations. However, no mutational activation of KIT or PDGFRA has been identified in pediatric gastric GISTs, neurofibromatosis-1-associated GISTs, and a small subset of sporadic GISTs in adults [so-called wild-type (WT) GISTs]. Recently, pediatric gastric GISTs and some adult WT gastric GISTs have been found to have losses of the succinate dehydrogenase (SDH) complex, a Krebs cycle/electron transport chain interface protein, as seen by immunohistochemical loss of SDH subunit B (SDHB) expression. Moreover, recently, expression of the receptor for type I insulin-like growth factor (IGF1R) has been detected in pediatric and WT GISTs, although only a small number of cases have been analyzed. In this study, IGF1R expression was examined immunohistochemically in 1078 well-characterized GISTs representing different clinicogenetic categories and in 103 non-GIST gastrointestinal tumors. IGF1R expression was detected in 71/80 of SDH-deficient GISTs (SDHB-negative GISTs) but only in 9/625 (1%) of the SDHB-positive gastric GISTs. The latter often carried KIT or PDGFRA mutations and generally occurred in older patients. None of the 373 intestinal GISTs was IGF1R positive, whereas many primary intestinal sarcomas, including clear cell sarcomas, leiomyosarcomas, and undifferentiated sarcomas, were IGF1R positive. The consistent lack of IGF1R expression in intestinal GISTs should be considered an additional immunohistochemical marker in the differential diagnosis between GISTs and non-GIST sarcomas. Because inhibition of IGF1R signaling might become a therapeutic target in GISTs, screening for IGF1R expression may become important in the near future.
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Affiliation(s)
- Jerzy Lasota
- Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20892, USA.
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31
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Benesch M, Wardelmann E, Leuschner I, Koscielniak E. Gastrointestinale Stromatumoren im Kindes- und Jugendalter. Monatsschr Kinderheilkd 2012. [DOI: 10.1007/s00112-012-2692-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Abstract
Succinate dehydrogenase-deficient gastrointestinal stromal tumors (GISTs) demonstrate unique pathological and clinical features, including the absence of activating mutations of KIT and PDGFRA, and primary resistance to imatinib. They arise exclusively in the stomach and account for 5-7.5% of all adult stomach GISTs and the great majority of these tumors in childhood. Insulin-like growth factor 1 receptor (IGF1R) overexpression has been associated with wild-type and pediatric GISTs. We propose that IGF1R overexpression is a feature of succinate dehydrogenase-deficient GISTs as a group. We assessed succinate dehydrogenase complex subunit B (SDHB) and IGF1R expression by immunohistochemistry in eight known succinate dehydrogenase-deficient GISTs, three GISTs arising in the setting of neurofibromatosis type 1 syndrome and 40 unselected GISTs. Selected KIT and PDGFRA exons were amplified and sequenced from formalin-fixed paraffin-embedded tumor samples. All eight succinate dehydrogenase-deficient tumors were wild-type for KIT and PDGFRA, succinate dehydrogenase B negative and demonstrated IGF1R overexpression. The three neurofibromatosis-related tumors were succinate dehydrogenase B positive and IGF1R negative. Of the 40 unselected upper GISTs, five were wild-type for KIT and PDGFRA in the selected exons. Two of the wild-type GISTs were succinate dehydrogenase B negative and showed IGF1R overexpression and three were succinate dehydrogenase B positive and IGF1R negative. We conclude that IGF1R overexpression is a feature of succinate dehydrogenase deficient GIST as a group, rather than pediatric or wild-type GIST per se. Therefore, IGF1R inhibition represents a potential rational therapeutic approach in this recently recognized subgroup of GIST.
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33
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Italiano A, Chen J, Zhang L, Hajdu M, Singer S, DeMatteo RP, Antonescu CR. Patterns of deregulation of insulin growth factor signalling pathway in paediatric and adult gastrointestinal stromal tumours. Eur J Cancer 2012; 48:3215-22. [PMID: 22770876 DOI: 10.1016/j.ejca.2012.05.021] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2012] [Revised: 05/11/2012] [Accepted: 05/22/2012] [Indexed: 12/17/2022]
Abstract
BACKGROUND Data regarding the patterns and the mechanisms of deregulation of the insulin growth factor (IGF) pathway in adult and paediatric gastrointestinal stromal tumours (GISTs) are limited. METHODS We investigated the expression profiling of the genes encoding the main components of the IGF signalling pathway in 131 GISTs (106 adults, 21 paediatric and four young adults) and 25 other soft-tissue sarcomas (STS) using an Affymetrix U133A platform. IGF2 was investigated for loss of imprinting (LOI) whereas IGF1R was analysed for copy number aberration and mutation. RESULTS IGF2 was the most highly overexpressed gene of the IGF pathway in GIST. IGF2 expression was also significantly higher than in other STS. IGF2 expression was correlated to the age onset and mutational status of GIST. Indeed, IGF2 expression was significantly higher in the 'adult' group than in the 'paediatric' and 'young adult' groups. Among adult GIST, IGF2 expression was higher in tumours lacking Homo sapiens v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) or alpha-type platelet-derived growth factor receptor (PDGFRA) mutations in comparison with mutated cases. A trend for a higher expression of IGF2 in resistant GIST in comparison to responsive GIST was also found. Overexpression of IGF2 was not related to LOI. Conversely, the expression of the IGF1R gene was significantly higher in the paediatric group than in the adult group. No copy number gains or mutations of IGF1R were observed. CONCLUSION The IGF pathway is deregulated in GIST with distinct patterns according to age onset and mutational status. The IGF pathway may represent a therapeutic target in patients with primary or secondary resistance to imatinib.
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Affiliation(s)
- Antoine Italiano
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
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Abstract
The IGF axis is a tightly controlled endocrine system that regulates cell growth and development, known to have an important function in cancer biology. IGF1 and IGF2 can promote cancer growth in a GH-independent manner both through paracrine and autocrine secretion and can also confer resistance to chemotherapy and radiation. Many alterations of this system have been found in neoplasias, including increased expression of ligands and receptors, loss of heterozygosity of the IGF2 locus and increased IGF1R gene copy number. The IGF1 network is an attractive candidate for targeted therapy, including receptor blockade with monoclonal antibodies and small molecule inhibitors of receptor downstream signaling. This article reviews the role of the IGF axis in the initiation and progression of cancer, and describes the recent advances in IGF inhibition as a therapeutic tool.
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Affiliation(s)
- Fernanda I Arnaldez
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10 CRC Room 1-3816, Bethesda, MD 20892, USA.
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Rikhof B, van der Graaf WTA, Suurmeijer AJH, van Doorn J, Meersma GJ, Groenen PJTA, Schuuring EMD, Meijer C, de Jong S. 'Big'-insulin-like growth factor-II signaling is an autocrine survival pathway in gastrointestinal stromal tumors. THE AMERICAN JOURNAL OF PATHOLOGY 2012; 181:303-12. [PMID: 22658485 DOI: 10.1016/j.ajpath.2012.03.028] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/23/2011] [Revised: 03/22/2012] [Accepted: 03/29/2012] [Indexed: 12/18/2022]
Abstract
New treatment targets need to be identified in gastrointestinal stromal tumors (GISTs) to extend the treatment options for patients experiencing failure with small-molecule tyrosine kinase inhibitors, such as imatinib. Insulin-like growth factor (IGF)-II acts as an autocrine factor in several tumor types by binding to IGF receptor type 1 (IGF-1R) and/or the insulin receptor (IR) isoform A. The aim of the present study was to investigate the putative role of unprocessed pro-IGF-II, called 'big'-IGF-II, in GISTs. The imatinib-sensitive GIST882 and imatinib-resistant GIST48 cell lines secrete high levels of big-IGF-II as demonstrated by ELISA and Western blotting analyses. IR isoform A mRNA and protein expression, but not that of IGF-1R, was found in these KIT mutant cell lines and in KIT and platelet-derived growth factor receptor α-mutant GIST specimens. Down-regulation of either big-IGF-II or IR affected AKT and MAPK signaling and reduced survival in both cell lines. Disruption of big-IGF-II signaling in combination with imatinib had additive cytotoxic effects on GIST882 cells. IGF-II mRNA as determined by in situ hybridization was present in 91% of 60 primary GISTs. Immunohistochemical analysis of big-IGF-II protein expression was associated with moderate- to high-risk tumors compared with tumors with a lower risk classification (P < 0.028). Our data put forth the big-IGF-II/IR isoform A axis as an autocrine survival pathway and potential therapeutic target in GISTs.
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Affiliation(s)
- Bart Rikhof
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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36
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Kwon O, Chung HY, Yu W, Bae HI, Chae YS, Kim JG, Kang BW, Lee WK. Clinical significance of insulin-like growth factor gene polymorphisms with survival in patients with gastrointestinal stromal tumors. JOURNAL OF THE KOREAN SURGICAL SOCIETY 2012; 82:288-95. [PMID: 22563535 PMCID: PMC3341477 DOI: 10.4174/jkss.2012.82.5.288] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/23/2011] [Revised: 03/14/2012] [Accepted: 03/21/2012] [Indexed: 11/30/2022]
Abstract
Purpose Insulin-like growth factors (IGFs) regulate a wide range of biological functions including cell proliferation, differentiation, and apoptosis through paracrine and autocrine mechanisms. Accordingly, the present study analyzed polymorphisms of IGF genes and their impact on the prognosis for patients with gastrointestinal stromal tumors (GISTs). Methods Two hundred-thirteen consecutive patients with GISTs who underwent curative surgery from 5 medical centers were enrolled in the present study. The genomic DNA was extracted from paraffin-embedded tumor tissue, and four IGF-1 (+2995C/A, +533C/T, IVS2-16540A/G, Ex4-177G/C) and one IGF-2 (IVS1+1280A/G) gene polymorphisms were determined using a Sequenom MassARRAY system. Results With a median follow-up of 18.4 months, the estimated 5-year relapse-free survival and overall survival rates were 69.9% and 86.7%, respectively. In a multivariate analysis including age, gender, primary site of disease, pathology, and risk stratification, no significant association was observed between the polymorphism of the IGF-1 and IGF-2 genes and survival. Conclusion None of the five IGF-1 and IGF-2 gene polymorphisms investigated in this study was found to be an independent prognostic marker for Korean patients with surgically resected GIST. However, further studies on a larger scale are warranted to clarify the role of IGF-1 and IGF-2 gene polymorphisms as a prognostic biomarker for GIST patients.
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Affiliation(s)
- Ohkyoung Kwon
- Department of Surgery, Kyungpook National University Medical Center, Kyungpook National University School of Medicine, Daegu, Korea
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Gastrointestinal stromal tumors (GISTs): CD117, DOG-1 and PKCθ expression. Is there any advantage in using several markers? Pathol Res Pract 2011; 208:74-81. [PMID: 22197035 DOI: 10.1016/j.prp.2011.11.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2011] [Revised: 10/31/2011] [Accepted: 11/24/2011] [Indexed: 01/01/2023]
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract. Expression of CD117, DOG1 and PKCθ was investigated immunohistochemically in a series of 99 paraffin-embedded GISTs in order to determine the sensitivity and diagnostic value of these markers. KIT exons 9, 11, 13 and 17 and PDGFRA exons 12 and 18 were amplified by PCR and sequenced. A total of 94/99 (94%) GISTs stained positive for CD117, 81/99 (82%) for PKCθ and 90/99 (91%) for DOG-1. A significant correlation was noted between CD117 and DOG-1 expression (p=0.0001). All three markers were expressed in 74% (73/99) of GISTs. Of the five CD117-negative cases, two were PKCθ-negative/DOG1-negative and had mutations in KIT exon 11. Two were PKCθ-positive/DOG1-positive and had mutations in PDGFRA (one each in exons 12 and 18), and one was DOG1-negative/PKCθ-positive, with a PDGFRA exon 18 mutation. The most sensitive marker was CD117, followed by DOG-1 and PKCθ. Although PKCθ was less sensitive, and its staining is more challenging and difficult to interpret, the use of this marker is highly recommended, particularly in CD117-negative/DOG-1-negative GISTs.
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Pappo AS, Janeway K, Laquaglia M, Kim SY. Special considerations in pediatric gastrointestinal tumors. J Surg Oncol 2011; 104:928-32. [PMID: 22069178 DOI: 10.1002/jso.21868] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Pediatric gastrointestinal tumors are rare in children but are being increasingly recognized. These tumors have distinct biologic and clinical feature that are different from those observed in adults. This review highlights the biological and clinical characteristics of pediatric GIST and provides diagnostic and therapeutic guidelines for the management these unique and challenging group of tumors.
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Affiliation(s)
- Alberto S Pappo
- St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
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A distinct pediatric-type gastrointestinal stromal tumor in adults: potential role of succinate dehydrogenase subunit A mutations. Am J Surg Pathol 2011; 35:1750-2. [PMID: 21997697 DOI: 10.1097/pas.0b013e318230a523] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Pantaleo MA, Astolfi A, Nannini M, Ceccarelli C, Formica S, Santini D, Heinrich MC, Corless C, Dei Tos AP, Paterini P, Catena F, Maleddu A, Saponara M, Di Battista M, Biasco G. Differential expression of neural markers in KIT and PDGFRA wild-type gastrointestinal stromal tumours. Histopathology 2011; 59:1071-80. [PMID: 22175887 DOI: 10.1111/j.1365-2559.2011.04071.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
AIMS To compare the genomic signatures of wild-type (WT) and mutated GISTs and the murine interstitial cells of Cajal (ICCs) to find markers of cell differentiation and other functions that may identify cells that give rise to WT tumours. METHODS AND RESULTS We analysed the gene expression profiles of a total of 30 tumour samples (four WT GISTs and 26 mutated GISTs), selected the genes most differentially expressed (P < 0.001:448 probe sets) and validated these results by quantitative polymerase chain reaction (PCR) and immunohistochemistry. In addition, we conducted a meta-analysis merging data from human GISTs with a genomic data set from murine ICCs. The gene expression profiles of WT and mutated GISTs differed profoundly, especially in the expression of those genes restricted primarily to neural tissues. We found that mature ICCs are more similar to mutated GISTs than WT GISTs. CONCLUSIONS WT GISTs have different genomic profiles from both mutated GISTs and murine mature ICCs. Considering that IGF1R expression is common to both WT GISTs and putative precursor ICCs, this study suggests that WT GISTs may derive either from ICCs at a different step of differentiation or from a different cell of origin.
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Affiliation(s)
- Maria A Pantaleo
- Department of Hematology and Oncology Sciences, L A Seragnoli, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
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Yang J, Ylipää A, Sun Y, Zheng H, Chen K, Nykter M, Trent J, Ratner N, Lev DC, Zhang W. Genomic and molecular characterization of malignant peripheral nerve sheath tumor identifies the IGF1R pathway as a primary target for treatment. Clin Cancer Res 2011; 17:7563-73. [PMID: 22042973 DOI: 10.1158/1078-0432.ccr-11-1707] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Malignant peripheral nerve sheath tumor (MPNST) is a rare sarcoma that lacks effective therapeutic strategies. We gain insight into the most recurrent genetically altered pathways with the purpose of scanning possible therapeutic targets. EXPERIMENTAL DESIGN We conducted a microarray-based comparative genomic hybridization profiling of two cohorts of primary MPNST tissue samples including 25 patients treated at The University of Texas MD Anderson Cancer Center and 26 patients from Tianjin Cancer Hospital. Immunohistochemistry (IHC) and cell biology detection and validation were carried out on human MPNST tissues and cell lines. RESULTS Genomic characterization of 51 MPNST tissue samples identified several frequently amplified regions harboring 2,599 genes and regions of deletion including 4,901 genes. At the pathway level, we identified a significant enrichment of copy number-altering events in the insulin-like growth factor 1 receptor (IGF1R) pathway, including frequent amplifications of the IGF1R gene itself. To validate the IGF1R pathway as a potential target in MPNSTs, we first confirmed that high IGF1R protein correlated with worse tumor-free survival in an independent set of samples using IHC. Two MPNST cell lines (ST88-14 and STS26T) were used to determine the effect of attenuating IGF1R. Inhibition of IGF1R in ST88-14 cells using siRNAs or an IGF1R inhibitor, MK-0646, led to significant decreases in cell proliferation, invasion, and migration accompanied by attenuation of the PI3K/AKT and mitogen-activated protein kinase pathways. CONCLUSION These integrated genomic and molecular studies provide evidence that the IGF1R pathway is a potential therapeutic target for patients with MPNST.
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Affiliation(s)
- Jilong Yang
- Departments of Bone and Soft Tissue Tumor, Pathology, and Epidemiology and Biostatistics, Tianjin Medical University Cancer Hospital and Institute, Tianjin, China.
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Ludwig JA, Lamhamedi-Cherradi SE, Lee HY, Naing A, Benjamin R. Dual targeting of the insulin-like growth factor and collateral pathways in cancer: combating drug resistance. Cancers (Basel) 2011; 3:3029-54. [PMID: 24212944 PMCID: PMC3759185 DOI: 10.3390/cancers3033029] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2011] [Revised: 07/06/2011] [Accepted: 07/19/2011] [Indexed: 12/18/2022] Open
Abstract
The insulin-like growth factor pathway, regulated by a complex interplay of growth factors, cognate receptors, and binding proteins, is critically important for many of the hallmarks of cancer such as oncogenesis, cell division, growth, and antineoplastic resistance. Naturally, a number of clinical trials have sought to directly abrogate insulin-like growth factor receptor 1 (IGF-1R) function and/or indirectly mitigate its downstream mediators such as mTOR, PI3K, MAPK, and others under the assumption that such therapeutic interventions would provide clinical benefit, demonstrable by impaired tumor growth as well as prolonged progression-free and overall survival for patients. Though a small subset of patients enrolled within phase I or II clinical trials revealed dramatic clinical response to IGF-1R targeted therapies (most using monoclonal antibodies to IGF-1R), in toto, the anticancer effect has been underwhelming and unsustained, as even those with marked clinical responses seem to rapidly acquire resistance to IGF-1R targeted agents when used alone through yet to be identified mechanisms. As the IGF-1R receptor is just one of many that converge upon common intracellular signaling cascades, it is likely that effective IGF-1R targeting must occur in parallel with blockade of redundant signaling paths. Herein, we present the rationale for dual targeting of IGF-1R and other signaling molecules as an effective strategy to combat acquired drug resistance by carcinomas and sarcomas.
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Affiliation(s)
- Joseph A. Ludwig
- Departments of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA; E-Mails: (S.L.C.); (R.B.)
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +1 (713) 792-3626; Fax: +1 (713) 794-1934
| | - Salah-Eddine Lamhamedi-Cherradi
- Departments of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA; E-Mails: (S.L.C.); (R.B.)
| | - Ho-Young Lee
- Departments of Thoracic Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA; E-Mail: (H.Y.L.)
| | - Aung Naing
- Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA; E-Mail: (A.N.)
| | - Robert Benjamin
- Departments of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA; E-Mails: (S.L.C.); (R.B.)
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Nannini M, Biasco G, Maleddu A, Pantaleo MA. New molecular targets beyond KIT and PDGFRA in gastrointestinal stromal tumors: present and future. Expert Opin Ther Targets 2011; 15:803-15. [DOI: 10.1517/14728222.2011.566215] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Gastrointestinal stromal tumours in children and young adults: A clinicopathologic series with long-term follow-up from the database of the Cooperative Weichteilsarkom Studiengruppe (CWS). Eur J Cancer 2011; 47:1692-8. [DOI: 10.1016/j.ejca.2011.03.014] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2010] [Revised: 02/03/2011] [Accepted: 03/11/2011] [Indexed: 12/13/2022]
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Abstract
This review aims to summarize recent knowledge gained about gastrointestinal stromal tumour (GIST) of particular relevance to histopathologists. KIT and PDGFRA mutation analyses can be useful for confirming a diagnosis of GIST, but there are some diagnostic limitations to these analyses, and so immunohistochemical markers currently remain crucial to the diagnostic process. Of these markers, CD117 and Discovered on GIST 1 (DOG1) are currently the most sensitive and specific markers of GIST, and recent data appear to disprove the fear that antigen retrieval causes false-positive CD117 immunostaining. The accurate prognostication of GIST has been greatly helped by the National Institutes of Health (NIH) and Armed Forces Institute of Pathology (AFIP) classification systems, although both systems still have limitations, and the behaviours of certain GIST subgroups are less well predicted by both systems. KIT and PDGFRA mutation analyses can help to predict the response of GISTs to receptor tyrosine kinase inhibitors, and both GISTs that respond and those that show resistance to these inhibitors may show characteristic pathological changes. Some GIST subgroups (e.g. Carney syndrome and paediatric GISTs) have had recently described clinicopathological and/or molecular characteristics which may help with the diagnosis and/or treatment of these specific neoplasms.
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Ganjoo KN, Patel S. Current and emerging pharmacological treatments for gastrointestinal stromal tumour. Drugs 2011; 71:321-30. [PMID: 21319869 DOI: 10.2165/11585370-000000000-00000] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Gastrointestinal stromal tumours (GIST) are the most common mesenchymal tumours of the gastrointestinal tract, previously classified as leiomyosarcomas. Most GIST express KIT and the majority have mutations in the KIT gene. The most common KIT mutation occurs in the juxtamembrane domain of exon 11. These mutations lead to cellular proliferation and survival. GIST with exon 11 mutations respond better to tyrosine kinase inhibitors (TKIs) than those with exon 9 mutations. Most KIT-negative GIST express platelet-derived growth factor receptor (PDGFR)-α; however, a small percentage of GIST are negative for both KIT and PDGFRα. Imatinib and other TKIs have dramatically improved the outcome of patients with metastatic GIST. Newer and more advanced TKIs are under intense investigation as eventually all GIST patients develop resistant tumours. In addition, these drugs can be utilized in the preoperative setting for patients with unresectable localized tumours or those at high risk for surgical morbidity. TKIs have been given in the adjuvant setting for patients with resected tumours at high risk for recurrence. The duration of adjuvant therapy is currently under evaluation; however, it is possible that these patients would need to continue therapy indefinitely.
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Affiliation(s)
- Kristen N Ganjoo
- Department of Medicine, Division of Oncology, Stanford Comprehensive Cancer Center, Stanford, California, USA.
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Pantaleo MA, Astolfi A, Indio V, Moore R, Thiessen N, Heinrich MC, Gnocchi C, Santini D, Catena F, Formica S, Martelli PL, Casadio R, Pession A, Biasco G. SDHA loss-of-function mutations in KIT-PDGFRA wild-type gastrointestinal stromal tumors identified by massively parallel sequencing. J Natl Cancer Inst 2011; 103:983-7. [PMID: 21505157 DOI: 10.1093/jnci/djr130] [Citation(s) in RCA: 121] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Approximately 10%-15% of gastrointestinal stromal tumors (GISTs) in adults do not harbor any mutation in the KIT or PDGFRA genes (ie, KIT/PDGFRA wild-type GISTs). Recently, mutations in SDHB and SDHC (which encode succinate dehydrogenase subunits B and C, respectively) but not in SDHA and SDHD (which encode subunits A and D, respectively) were identified in KIT/PDGFRA wild-type GISTs. To search for novel pathogenic mutations, we sequenced the tumor transcriptome of two young adult patients who developed sporadic KIT/PDGFRA wild-type GISTs by using a massively parallel sequencing approach. The only variants identified as disease related by computational analysis were in SDHA. One patient carried the homozygous nonsense mutation p.Ser384X, the other patient was a compound heterozygote harboring a p.Arg31X nonsense mutation and a p.Arg589Trp missense mutation. The heterozygous nonsense mutations in both patients were present in germline DNA isolated from peripheral blood. Protein structure analysis indicates that all three mutations lead to functional inactivation of the protein. This is the first report, to our knowle dge, that identifies SDHA inactivation as a common oncogenic event in GISTs that lack a mutation in KIT and PDGFRA.
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Affiliation(s)
- Maria A Pantaleo
- Department of Hematology and Oncological Sciences "L.A.Seragnoli," Sant'Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy.
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[Gastrointestinal stromal tumours in pediatrics: a summary of the literature on this orphan disease]. Bull Cancer 2011; 98:79-86. [PMID: 21300610 DOI: 10.1684/bdc.2010.1296] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Recommendations for the management of gastrointestinal stromal tumours (GIST) in children and adolescents do presently not exist. Thus, a summary of the current literature was conducted serving as a basis for the development of optimal management strategies for childhood GIST. Pediatric cases of GIST may occur sporadically, or within a predisposition syndrome such as Carney triad or Carney-Stratakis syndrome. Moreover, cases with familial GIST have been reported. The frequency of mutations of the oncogenes KIT and PDGFRα in sporadic GIST is substantially lower as compared with adults with GIST. An international prospective registration based on national registries has recently been started in order to acquire more clinical and molecular data and to develop appropriate management strategies for children and adolescents with GIST.
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Pantaleo MA, Nicoletti G, Nanni C, Gnocchi C, Landuzzi L, Quarta C, Boschi S, Nannini M, Di Battista M, Castellucci P, Fanti S, Lollini PL, Bellan E, Castelli M, Rubello D, Biasco G. Preclinical evaluation of KIT/PDGFRA and mTOR inhibitors in gastrointestinal stromal tumors using small animal FDG PET. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2010; 29:173. [PMID: 21192792 PMCID: PMC3022678 DOI: 10.1186/1756-9966-29-173] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2010] [Accepted: 12/30/2010] [Indexed: 01/15/2023]
Abstract
Background Primary and secondary drug resistance to imatinib and sunitinib in patients with gastrointestinal stromal tumors (GISTs) has led to a pressing need for new therapeutic strategies such as drug combinations. Most GISTs are caused by mutations in the KIT receptor, leading to upregulated KIT tyrosine kinase activity. Imatinib and nilotinib directly inhibit the kinase activity of KIT, while RAD001 (everolimus) inhibits mTOR. We report a preclinical study on drug combinations in a xenograft model of GIST in which effects on tumor dimensions and metabolic activity were assessed by small animal PET imaging. Methods Rag2-/-; γcommon -/- male mice were injected s.c. into the right leg with GIST 882. The animals were randomized into 6 groups of 6 animals each for different treatment regimens: No therapy (control), imatinib (150 mg/kg b.i.d.) by oral gavage for 6 days, then once/day for another 7 days, everolimus (10 mg/kg/d.) by oral gavage, everolimus (10 mg/kg/d.) + imatinib (150 mg/kg b.i.d.) by oral gavage for 6 days, then once/day for another 7 days, nilotinib (75 mg/kg/d.) by oral gavage, nilotinib (75 mg/kg/d.) + imatinib (150 mg/kg b.i.d) by oral gavage for 6 days, then once/day for another 7 days. Tumor growth control was evaluated by measuring tumor volume (cm3). Small animal PET (GE Explore tomography) was used to evaluate tumor metabolism and performed in one animal per group at base-line then after 4 and 13 days of treatment. Results After a median latency time of 31 days, tumors grew in all animals (volume 0,06-0,15 cm3) and the treatments began at day 38 after cell injection. Tumor volume control (cm3) after 13 days of treatment was > 0.5 for imatinib alone and nilotinib alone, and < 0.5 for the 2 combinations of drugs and for everolimus alone. The baseline FDG uptake was positive in all animals. FDG/SUV/TBR was strongly reduced over time by everolimus both as a single agent and in combination with imatinib respectively: 3.1 vs. 2.3 vs. 1.9 and 2.5 vs 2.3 vs 0. Conclusions As single agents, all drugs showed an anti-tumor effect in GIST xenografts but everolimus was superior. The everolimus plus imatinib combination appeared to be the most active regimen both in terms of inhibiting tumor growth and tumor metabolism. The integration of everolimus in GIST treatment merits further investigation.
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Affiliation(s)
- Maria Abbondanza Pantaleo
- Department of Hematology and Oncology Sciences L. A. Seragnoli, Sant' Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy.
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qPCR in gastrointestinal stromal tumors: Evaluation of reference genes and expression analysis of KIT and the alternative receptor tyrosine kinases FLT3, CSF1-R, PDGFRB, MET and AXL. BMC Mol Biol 2010; 11:100. [PMID: 21171987 PMCID: PMC3014927 DOI: 10.1186/1471-2199-11-100] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2010] [Accepted: 12/20/2010] [Indexed: 12/27/2022] Open
Abstract
Background Gastrointestinal stromal tumors (GIST) represent the most common mesenchymal tumors of the gastrointestinal tract. About 85% carry an activating mutation in the KIT or PDGFRA gene. Approximately 10% of GIST are so-called wild type GIST (wt-GIST) without mutations in the hot spots. In the present study we evaluated appropriate reference genes for the expression analysis of formalin-fixed, paraffin-embedded and fresh frozen samples from gastrointestinal stromal tumors. We evaluated the gene expression of KIT as well as of the alternative receptor tyrosine kinase genes FLT3, CSF1-R, PDGFRB, AXL and MET by qPCR. wt-GIST were compared to samples with mutations in KIT exon 9 and 11 and PDGFRA exon 18 in order to evaluate whether overexpression of these alternative RTK might contribute to the pathogenesis of wt-GIST. Results Gene expression variability of the pooled cDNA samples is much lower than the single reverse transcription cDNA synthesis. By combining the lowest variability values of fixed and fresh tissue, the genes POLR2A, PPIA, RPLPO and TFRC were chosen for further analysis of the GIST samples. Overexpression of KIT compared to the corresponding normal tissue was detected in each GIST subgroup except in GIST with PDGFRA exon 18 mutation. Comparing our sample groups, no significant differences in the gene expression levels of FLT3, CSF1R and AXL were determined. An exception was the sample group with KIT exon 9 mutation. A significantly reduced expression of CSF1R, FLT3 and PDGFRB compared to the normal tissue was detected. GIST with mutations in KIT exon 9 and 11 and in PDGFRA exon 18 showed a significant PDGFRB downregulation. Conclusions As the variability of expression levels for the reference genes is very high comparing fresh frozen and formalin-fixed tissue there is a strong need for validation in each tissue type. None of the alternative receptor tyrosine kinases analyzed is associated with the pathogenesis of wild-type or mutated GIST. It remains to be clarified whether an autocrine or paracrine mechanism by overexpression of receptor tyrosine kinase ligands is responsible for the tumorigenesis of wt-GIST.
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