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Boichuk S, Dunaev P, Galembikova A, Valeeva E. Fibroblast Growth Factor 2 (FGF2) Activates Vascular Endothelial Growth Factor (VEGF) Signaling in Gastrointestinal Stromal Tumors (GIST): An Autocrine Mechanism Contributing to Imatinib Mesylate (IM) Resistance. Cancers (Basel) 2024; 16:3103. [PMID: 39272961 PMCID: PMC11394061 DOI: 10.3390/cancers16173103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Revised: 08/29/2024] [Accepted: 09/04/2024] [Indexed: 09/15/2024] Open
Abstract
We showed previously that the autocrine activation of the FGFR-mediated pathway in GIST lacking secondary KIT mutations was a result of the inhibition of KIT signaling. We show here that the FGF2/FGFR pathway regulates VEGF-A/VEGFR signaling in IM-resistant GIST cells. Indeed, recombinant FGF2 increased the production of VEGF-A by IM-naive and resistant GIST cells. VEGF-A production was also increased in KIT-inhibited GIST, whereas the neutralization of FGF2 by anti-FGF2 mAb attenuated VEGFR signaling. Of note, BGJ 398, pan FGFR inhibitor, effectively and time-dependently inhibited VEGFR signaling in IM-resistant GIST T-1R cells, thereby revealing the regulatory role of the FGFR pathway in VEGFR signaling for this particular GIST cell line. This also resulted in significant synergy between BGJ 398 and VEGFR inhibitors (i.e., sunitinib and regorafenib) by enhancing their pro-apoptotic and anti-proliferative activities. The high potency of the combined use of VEGFR and FGFR inhibitors in IM-resistant GISTs was revealed by the impressive synergy scores observed for regorafenib or sunitinib and BGJ 398. Moreover, FGFR1/2 and VEGFR1/2 were co-localized in IM-resistant GIST T-1R cells, and the direct interaction between the aforementioned RTKs was confirmed by co-immunoprecipitation. In contrast, IM-resistant GIST 430 cells expressed lower basal levels of FGF2 and VEGF-A. Despite the increased expression VEGFR1 and FGFR1/2 in GIST 430 cells, these RTKs were not co-localized and co-immunoprecipitated. Moreover, no synergy between FGFR and VEGFR inhibitors was observed for the IM-resistant GIST 430 cell line. Collectively, the dual targeting of FGFR and VEGFR pathways in IM-resistant GISTs is not limited to the synergistic anti-angiogenic treatment effects. The dual inhibition of FGFR and VEGFR pathways in IM-resistant GISTs potentiates the proapoptotic and anti-proliferative activities of the corresponding RTKi. Mechanistically, the FGF2-induced activation of the FGFR pathway turns on VEGFR signaling via the overproduction of VEGF-A, induces the interaction between FGFR1/2 and VEGFR1, and thereby renders cancer cells highly sensitive to the dual inhibition of the aforementioned RTKs. Thus, our data uncovers the novel mechanism of the cross-talk between the aforementioned RTKs in IM-resistant GISTs lacking secondary KIT mutations and suggests that the dual blockade of FGFR and VEGFR signaling might be an effective treatment strategy for patients with GIST-acquired IM resistance via KIT-independent mechanisms.
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Affiliation(s)
- Sergei Boichuk
- Department of Pathology, Kazan State Medical University, Kazan 420012, Russia
- Department of Radiotherapy and Radiology, Faculty of Surgery, Russian Medical Academy of Continuous Professional Education, Moscow 125993, Russia
- "Biomarker" Research Laboratory, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia
| | - Pavel Dunaev
- Department of Pathology, Kazan State Medical University, Kazan 420012, Russia
| | - Aigul Galembikova
- Department of Pathology, Kazan State Medical University, Kazan 420012, Russia
| | - Elena Valeeva
- Central Research Laboratory, Kazan State Medical University, Kazan 420012, Russia
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Popoiu TA, Pîrvu CA, Popoiu CM, Iacob ER, Talpai T, Voinea A, Albu RS, Tãban S, Bãlãnoiu LM, Pantea S. Gastrointestinal Stromal Tumors (GISTs) in Pediatric Patients: A Case Report and Literature Review. CHILDREN (BASEL, SWITZERLAND) 2024; 11:1040. [PMID: 39334573 PMCID: PMC11429550 DOI: 10.3390/children11091040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 08/18/2024] [Accepted: 08/23/2024] [Indexed: 09/30/2024]
Abstract
Gastrointestinal stromal tumors (GISTs) are rare mesenchymal neoplasms that primarily affect adults, with pediatric cases constituting only 0.5-2.7% of the total. Pediatric GISTs present unique clinical, genetic, and pathological features that distinguish them from adult cases. This literature review aims to elucidate these differences, emphasizing diagnostic and therapeutic challenges. We discuss the resistance of pediatric GISTs to conventional chemotherapy and highlight the importance of surgical intervention, especially in emergency situations involving intra-abdominal bleeding. The review also explores the molecular characteristics of pediatric GISTs, including rare mutations such as quadruple-negative wild-type GIST with an FGF3 gene gain mutation. To illustrate these points, we conclude with a case from our clinic involving a 15-year-old female with multiple CD117-positive gastric GISTs and a quadruple-negative wild-type genetic profile who required urgent surgical intervention following a failed tumor embolization. This case underscores the critical need for early diagnosis and individualized therapeutic strategies combining oncologic and surgical care to improve outcomes in pediatric GIST patients.
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Affiliation(s)
- Tudor-Alexandru Popoiu
- Department of General Surgery, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
- Department III of Functional Sciences, Discipline of Medical Informatics and Biostatistics, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Cãtãlin-Alexandru Pîrvu
- Department of General Surgery, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Cãlin-Marius Popoiu
- Department of Pediatric Surgery, "Victor Babes" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Emil Radu Iacob
- Department of Pediatric Surgery, "Victor Babes" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Tamas Talpai
- Department of General Surgery, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Amalia Voinea
- Department of General Surgery, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Rãzvan-Sorin Albu
- Department of General Surgery, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Sorina Tãban
- Department of Pathology, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Larisa-Mihaela Bãlãnoiu
- Department of General Surgery, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Stelian Pantea
- Department of General Surgery, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
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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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Trembath HE, Yeh JJ, Lopez NE. Gastrointestinal Malignancy: Genetic Implications to Clinical Applications. Cancer Treat Res 2024; 192:305-418. [PMID: 39212927 DOI: 10.1007/978-3-031-61238-1_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Advances in molecular genetics have revolutionized our understanding of the pathogenesis, progression, and therapeutic options for treating gastrointestinal (GI) cancers. This chapter provides a comprehensive overview of the molecular landscape of GI cancers, focusing on key genetic alterations implicated in tumorigenesis across various anatomical sites including GIST, colon and rectum, and pancreas. Emphasis is placed on critical oncogenic pathways, such as mutations in tumor suppressor genes, oncogenes, chromosomal instability, microsatellite instability, and epigenetic modifications. The role of molecular biomarkers in predicting prognosis, guiding treatment decisions, and monitoring therapeutic response is discussed, highlighting the integration of genomic profiling into clinical practice. Finally, we address the evolving landscape of precision oncology in GI cancers, considering targeted therapies and immunotherapies.
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Affiliation(s)
- Hannah E Trembath
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA
| | - Jen Jen Yeh
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA
| | - Nicole E Lopez
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA.
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA.
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Boichuk S, Dunaev P, Skripova V, Galembikova A, Bikinieva F, Shagimardanova E, Gazizova G, Deviatiiarov R, Valeeva E, Mikheeva E, Vasilyeva M, Kopnin P, Strelnikov V, Kiyamova R. Unraveling the Mechanisms of Sensitivity to Anti-FGF Therapies in Imatinib-Resistant Gastrointestinal Stromal Tumors (GIST) Lacking Secondary KIT Mutations. Cancers (Basel) 2023; 15:5354. [PMID: 38001614 PMCID: PMC10670741 DOI: 10.3390/cancers15225354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 11/03/2023] [Accepted: 11/06/2023] [Indexed: 11/26/2023] Open
Abstract
We showed previously that inhibition of KIT signaling in GISTs activates FGFR-signaling pathway rendering cancer cells resistant to receptor tyrosine kinase inhibitor (RTKi) imatinib mesylate (IM) (Gleevec) despite of absence of secondary KIT mutations and thereby illustrating a rationale for the combined (e.g., KIT- and FGFR-targeted) therapies. We show here that long-term culture of IM-resistant GISTs (GIST-R1) with IM substantially down-regulates KIT expression and induces activation of the FGFR-signaling cascade, evidenced by increased expression of total and phosphorylated forms of FGFR1 and 2, FGF-2, and FRS-2, the well-known adaptor protein of the FGF-signaling cascade. This resulted in activation of both AKT- and MAPK-signaling pathways shown on mRNA and protein levels, and rendered cancer cells highly sensitive to pan-FGFR-inhibitors (BGJ 398, AZD 4547, and TAS-120). Indeed, we observed a significant decrease of IC50 values for BGJ 398 in the GIST subclone (GIST-R2) derived from GIST-R1 cells continuously treated with IM for up to 12 months. An increased sensitivity of GIST-R2 cells to FGFR inhibition was also revealed on the xenograft models, illustrating a substantial (>70%) decrease in tumor size in BGJ 398-treated animals when treated with this pan-FGFR inhibitor. Similarly, an increased intra-tumoral apoptosis as detected by immunohistochemical (IHC)-staining for cleaved caspase-3 on day 5 of the treatment was found. As expected, both BGJ 398 and IM used alone lacked the pro-apoptotic and growth-inhibitory activities on GIST-R1 xenografts, thereby revealing their resistance to these TKis when used alone. Important, the knockdown of FGFR2, and, in much less content, FGF-2, abrogated BGJ 398's activity against GIST-R2 cells both in vitro and in vivo, thereby illustrating the FGF-2/FGFR2-signaling axis in IM-resistant GISTs as a primary molecular target for this RTKi. Collectively, our data illustrates that continuous inhibition of KIT signaling in IM-resistant GISTs lacking secondary KIT mutations induced clonal heterogeneity of GISTs and resulted in accumulation of cancer cells with overexpressed FGF-2 and FGFR1/2, thereby leading to activation of FGFR-signaling. This in turn rendered these cells extremely sensitive to the pan-FGFR inhibitors used in combination with IM, or even alone, and suggests a rationale to re-evaluate the effectiveness of FGFR-inhibitors in order to improve the second-line therapeutic strategies for selected subgroups of GIST patients (e.g., IM-resistant GISTs lacking secondary KIT mutations and exhibiting the activation of the FGFR-signaling pathway).
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Affiliation(s)
- Sergei Boichuk
- Department of Pathology, Kazan State Medical University, Kazan 420012, Russia; (P.D.); (A.G.); (F.B.); (E.M.)
- Department of Radiotherapy and Radiology, Russian Medical Academy of Continuous Professional Education, Moscow 127051, Russia
- Central Research Laboratory, Kazan State Medical University, Kazan 420012, Russia;
- Biomarker Research Laboratory, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia; (V.S.); (R.K.)
| | - Pavel Dunaev
- Department of Pathology, Kazan State Medical University, Kazan 420012, Russia; (P.D.); (A.G.); (F.B.); (E.M.)
| | - Vera Skripova
- Biomarker Research Laboratory, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia; (V.S.); (R.K.)
| | - Aigul Galembikova
- Department of Pathology, Kazan State Medical University, Kazan 420012, Russia; (P.D.); (A.G.); (F.B.); (E.M.)
| | - Firyuza Bikinieva
- Department of Pathology, Kazan State Medical University, Kazan 420012, Russia; (P.D.); (A.G.); (F.B.); (E.M.)
| | - Elena Shagimardanova
- Regulatory Genomics Research Center, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia; (E.S.); (G.G.); (R.D.)
- LIFT—Life Improvement by Future Technologies Institute, Moscow 121205, Russia
- Loginov Moscow Clinical Scientific Center, Moscow 111123, Russia
| | - Guzel Gazizova
- Regulatory Genomics Research Center, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia; (E.S.); (G.G.); (R.D.)
| | - Ruslan Deviatiiarov
- Regulatory Genomics Research Center, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia; (E.S.); (G.G.); (R.D.)
- LIFT—Life Improvement by Future Technologies Institute, Moscow 121205, Russia
| | - Elena Valeeva
- Central Research Laboratory, Kazan State Medical University, Kazan 420012, Russia;
| | - Ekaterina Mikheeva
- Department of Pathology, Kazan State Medical University, Kazan 420012, Russia; (P.D.); (A.G.); (F.B.); (E.M.)
| | - Maria Vasilyeva
- Cytogenetics Laboratory, Carcinogenesis Institute, N.N. Blokhin National Medical Research Center of Oncology, Moscow 115478, Russia; (M.V.); (P.K.)
| | - Pavel Kopnin
- Cytogenetics Laboratory, Carcinogenesis Institute, N.N. Blokhin National Medical Research Center of Oncology, Moscow 115478, Russia; (M.V.); (P.K.)
| | - Vladimir Strelnikov
- Epigenetics Laboratory, Research Centre for Medical Genetics, Moscow 115522, Russia;
| | - Ramziya Kiyamova
- Biomarker Research Laboratory, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia; (V.S.); (R.K.)
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Fan Z, Zhang L, Zhang S, Liu A, Li S, Cao X, Tian J, Zhao S, Sun J. Farnesyltransferase (FTase) Inhibitors Increase Inhibition of KIT Mutants by Imatinib. Rep Biochem Mol Biol 2023; 12:74-82. [PMID: 37724142 PMCID: PMC10505455 DOI: 10.52547/rbmb.12.1.74] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Accepted: 12/19/2022] [Indexed: 09/20/2023]
Abstract
Background Mutations in the receptor tyrosine kinase KIT are the major cause of gastrointestinal stromal tumors. KIT-mediated activation of the RAS/RAF/MEK/ERK and PI3 kinase/AKT pathways plays an important role in KIT mutant-mediated cell transformation. Methods The frequently seen primary KIT mutations W557K558del and V560D, and the secondary KIT mutations V654A and N822K, in gastrointestinal stromal tumors were stably transfected into Ba/F3 cells. Cell proliferation was examined with a CCK kit, and cell survival and cell cycle were examined by flow cytometry. Cell signaling was examined by western blot. Results We found that farnesyltransferase inhibitors tipifarnib and lonafarnib, which inhibit RAS activity, inhibited ERK activation mediated by both wild-type and KIT mutants, which often occur in gastrointestinal stromal tumors. Correspondingly, both wild-type and KIT mutant-mediated cell survival and proliferation were inhibited by both inhibitors. Imatinib is used as the first-line targeted therapy for gastrointestinal stromal tumors in the clinic. In our study, both inhibitors increased imatinib-mediated inhibition of cell survival and proliferation induced by both wild-type and KIT mutants. Similar to the primary KIT mutations, secondary mutations of KIT-induced ERK activation and cell response were inhibited by both inhibitors. Conclusions Our results suggested the potential benefit of farnesyltransferase inhibitors either alone or combined with imatinib in the treatment of gastrointestinal stromal tumors carrying KIT mutations.
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Affiliation(s)
- Zhaoyang Fan
- NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China.
| | - Liangying Zhang
- NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China.
| | - Shaoting Zhang
- NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China.
| | - Anbu Liu
- NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China.
| | - Shujing Li
- NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China.
- General Hospital of Ningxia Medical University, Yinchuan, China.
| | - Xu Cao
- NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China.
| | - Jinhai Tian
- NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China.
- General Hospital of Ningxia Medical University, Yinchuan, China.
| | - Sien Zhao
- NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China.
| | - Jianmin Sun
- NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Science and Technology Center, School of Basic Medicine, Ningxia Medical University, Yinchuan, China.
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Salmikangas S, Böhling T, Merikoski N, Jagdeo J, Sampo M, Vesterinen T, Sihto H. Tensin2 Is a Novel Diagnostic Marker in GIST, Associated with Gastric Location and Non-Metastatic Tumors. Cancers (Basel) 2022; 14:3212. [PMID: 35804982 PMCID: PMC9265085 DOI: 10.3390/cancers14133212] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 06/23/2022] [Accepted: 06/27/2022] [Indexed: 12/10/2022] Open
Abstract
GIST is a rare soft tissue sarcoma, for which KIT and DOG1 are used as highly sensitive diagnostic markers. Other diagnostic markers include CD34, protein kinase C θ, deficiency of succinate dehydrogenase complex subunit B, carbonic anhydrase II, and type I insulin-like growth factor receptor. We investigated the role of TNS2 as a diagnostic biomarker by using immunohistochemistry in 176 GISTs and 521 other sarcomas. All GISTs expressed TNS2, with intermediate or high expression in 71.4% of samples. The majority (89.8%) of other sarcomas were negative for TNS2, and intermediate to strong staining was only seen in 2.9% of samples. Strong TNS2 staining was associated with gastric location (gastric 52.8% vs. non-gastric 7.2%; p < 0.001), absence of metastases (non-metastatic tumors 44.3% vs. metastatic tumors 5.9%; p = 0.004), female sex (female 45.9% vs. male 33.8%; p = 0.029), and tumors of lower risk categories (very low or low 46.9% vs. intermediate 51.7% vs. high 29.0%; p = 0.020). TNS2 expression did not correlate with overall survival or metastasis-free survival. No associations between TNS2 expression and KIT/PDGFRA mutation status, tumor size, mitotic count, or age of the patient were detected. The results provide conclusive evidence for the value of TNS2 as a sensitive and specific diagnostic biomarker for GIST.
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Affiliation(s)
- Sami Salmikangas
- Department of Pathology, University of Helsinki and Helsinki University Hospital, FI-00014 Helsinki, Finland; (T.B.); (N.M.); (J.J.); (H.S.)
| | - Tom Böhling
- Department of Pathology, University of Helsinki and Helsinki University Hospital, FI-00014 Helsinki, Finland; (T.B.); (N.M.); (J.J.); (H.S.)
| | - Nanna Merikoski
- Department of Pathology, University of Helsinki and Helsinki University Hospital, FI-00014 Helsinki, Finland; (T.B.); (N.M.); (J.J.); (H.S.)
| | - Joanna Jagdeo
- Department of Pathology, University of Helsinki and Helsinki University Hospital, FI-00014 Helsinki, Finland; (T.B.); (N.M.); (J.J.); (H.S.)
| | - Mika Sampo
- Department of Pathology, HUSLAB, HUS Diagnostic Center, University of Helsinki and Helsinki University Hospital, FI-00029 Helsinki, Finland; (M.S.); (T.V.)
| | - Tiina Vesterinen
- Department of Pathology, HUSLAB, HUS Diagnostic Center, University of Helsinki and Helsinki University Hospital, FI-00029 Helsinki, Finland; (M.S.); (T.V.)
| | - Harri Sihto
- Department of Pathology, University of Helsinki and Helsinki University Hospital, FI-00014 Helsinki, Finland; (T.B.); (N.M.); (J.J.); (H.S.)
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Zhang F, Altindis E, Kahn CR, DiMarchi RD, Gelfanov V. A viral insulin-like peptide is a natural competitive antagonist of the human IGF-1 receptor. Mol Metab 2021; 53:101316. [PMID: 34400347 PMCID: PMC8621328 DOI: 10.1016/j.molmet.2021.101316] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 08/03/2021] [Accepted: 08/10/2021] [Indexed: 12/01/2022] Open
Abstract
OBJECTIVE Natural sources of molecular diversity remain of utmost importance as a reservoir of proteins and peptides with unique biological functions. We recently identified such a family of viral insulin-like peptides (VILPs). We sought to advance the chemical methods in synthesis to explore the structure-function relationship within these VILPs, and the molecular basis for differential biological activities relative to human IGF-1 and insulin. METHODS Optimized chemical methods in synthesis were established for a set of VILPs and related analogs. These modified forms included the substitution of select VILP chains with those derived from human insulin and IGF-1. Each peptide was assessed in vitro for agonism and antagonism at the human insulin and the human insulin-like growth factor 1 receptor (IGF-1R). RESULTS We report here that one of these VILPs, lymphocystis disease virus-1 (LCDV1)-VILP, has the unique property to be a potent and full antagonist of the IGF-1R. We demonstrate the coordinated importance of the B- and C-chains of the VILP in regulating this activity. Moreover, mutation of the glycine following the first cysteine in the B-chain of IGF-1 to serine, in concert with substitution to the connecting peptide of LCDV1-VILP, converted native IGF-1 to a high potency antagonist. CONCLUSIONS The results reveal novel aspects in ligand-receptor interactions at the IGF-1 receptor and identify a set of antagonists of potential medicinal importance.
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Affiliation(s)
- Fa Zhang
- Department of Chemistry, Indiana University, Bloomington, IN, 47405, USA
| | - Emrah Altindis
- Boston College Biology Department, Chestnut Hill, MA, 02467, USA
| | - C Ronald Kahn
- Joslin Diabetes Center, Harvard Medical School, Boston, MA, 02215, USA
| | - Richard D DiMarchi
- Department of Chemistry, Indiana University, Bloomington, IN, 47405, USA.
| | - Vasily Gelfanov
- Novo Nordisk Research Center, 5225 Exploration Drive, Indianapolis, IN, 46241, USA
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Unraveling the IGF System Interactome in Sarcomas Exploits Novel Therapeutic Options. Cells 2021; 10:cells10082075. [PMID: 34440844 PMCID: PMC8392407 DOI: 10.3390/cells10082075] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Revised: 08/06/2021] [Accepted: 08/10/2021] [Indexed: 12/15/2022] Open
Abstract
Aberrant bioactivity of the insulin-like growth factor (IGF) system results in the development and progression of several pathologic conditions including cancer. Preclinical studies have shown promising anti-cancer therapeutic potentials for anti-IGF targeted therapies. However, a clear but limited clinical benefit was observed only in a minority of patients with sarcomas. The molecular complexity of the IGF system, which comprises multiple regulators and interactions with other cancer-related pathways, poses a major limitation in the use of anti-IGF agents and supports the need of combinatorial therapeutic strategies to better tackle this axis. In this review, we will initially highlight multiple mechanisms underlying IGF dysregulation in cancer and then focus on the impact of the IGF system and its complexity in sarcoma development and progression as well as response to anti-IGF therapies. We will also discuss the role of Ephrin receptors, Hippo pathway, BET proteins and CXCR4 signaling, as mediators of sarcoma malignancy and relevant interactors with the IGF system in tumor cells. A deeper understanding of these molecular interactions might provide the rationale for novel and more effective therapeutic combinations to treat sarcomas.
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10
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D'Alpino Peixoto R, Medeiros BA, Cronemberger EH. Resected High-Risk Rectal GIST Harboring NTRK1 Fusion: a Case Report and Review of the Literature. J Gastrointest Cancer 2021; 52:316-319. [PMID: 32506289 DOI: 10.1007/s12029-020-00423-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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LeRoith D, Holly JMP, Forbes BE. Insulin-like growth factors: Ligands, binding proteins, and receptors. Mol Metab 2021; 52:101245. [PMID: 33962049 PMCID: PMC8513159 DOI: 10.1016/j.molmet.2021.101245] [Citation(s) in RCA: 133] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 04/09/2021] [Accepted: 04/28/2021] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND The insulin-like growth factor family of ligands (IGF-I, IGF-II, and insulin), receptors (IGF-IR, M6P/IGF-IIR, and insulin receptor [IR]), and IGF-binding proteins (IGFBP-1-6) play critical roles in normal human physiology and disease states. SCOPE OF REVIEW Insulin and insulin receptors are the focus of other chapters in this series and will therefore not be discussed further. Here we review the basic components of the IGF system, their role in normal physiology and in critical pathology's. While this review concentrates on the role of IGFs in human physiology, animal models have been essential in providing understanding of the IGF system, and its regulation, and are briefly described. MAJOR CONCLUSIONS IGF-I has effects via the circulation and locally within tissues to regulate cellular growth, differentiation, and survival, thereby controlling overall body growth. IGF-II levels are highest prenatally when it has important effects on growth. In adults, IGF-II plays important tissue-specific roles, including the maintenance of stem cell populations. Although the IGF-IR is closely related to the IR it has distinct physiological roles both on the cell surface and in the nucleus. The M6P/IGF-IIR, in contrast, is distinct and acts as a scavenger by mediating internalization and degradation of IGF-II. The IGFBPs bind IGF-I and IGF-II in the circulation to prolong their half-lives and modulate tissue access, thereby controlling IGF function. IGFBPs also have IGF ligand-independent cell effects.
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Affiliation(s)
- Derek LeRoith
- Division of Endocrinology, Diabetes and Bone Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jeff M P Holly
- Translational Health Sciences, Bristol Medical School, Learning & Research Building, Southmead Hospital, Bristol, BS10 5NB, UK.
| | - Briony E Forbes
- Discipline of Medical Biochemistry, Flinders Health and Medical Research Institute, Flinders University, Bedford Park, 5042, Australia
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Abstract
Gastrointestinal stromal tumours (GIST) have an incidence of ~1.2 per 105 individuals per year in most countries. Around 80% of GIST have varying molecular changes, predominantly mutually exclusive activating KIT or PDGFRA mutations, but other, rare subtypes also exist. Localized GIST are curable, and surgery is their standard treatment. Risk factors for relapse are tumour size, mitotic index, non-gastric site and tumour rupture. Patients with GIST with KIT or PDGFRA mutations sensitive to the tyrosine kinase inhibitor (TKI) imatinib that are at high risk of relapse have improved survival with adjuvant imatinib treatment. In advanced disease, median overall survival has improved from 18 months to >70 months since the introduction of TKIs. The role of surgery in the advanced setting remains unclear. Resistance to TKIs arise mainly from subclonal selection of cells with resistance mutations in KIT or PDGFRA when they are the primary drivers. Advanced resistant GIST respond to second-line sunitinib and third-line regorafenib, as well as to the new broad-spectrum TKI ripretinib. Rare molecular forms of GIST with alterations involving NF1, SDH genes, BRAF or NTRK genes generally show primary resistance to standard TKIs, but some respond to specific inhibitors of the activated genes. Despite major advances, many questions in both advanced and localized disease remain unanswered.
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Affiliation(s)
- Jean-Yves Blay
- Department of Medicine, Centre Leon Berard, UNICANCER & University Lyon I, Lyon, France.
| | - Yoon-Koo Kang
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Toshiroo Nishida
- Surgery Department, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
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Novel Regulators of the IGF System in Cancer. Biomolecules 2021; 11:biom11020273. [PMID: 33673232 PMCID: PMC7918569 DOI: 10.3390/biom11020273] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 02/05/2021] [Accepted: 02/09/2021] [Indexed: 02/07/2023] Open
Abstract
The insulin-like growth factor (IGF) system is a dynamic network of proteins, which includes cognate ligands, membrane receptors, ligand binding proteins and functional downstream effectors. It plays a critical role in regulating several important physiological processes including cell growth, metabolism and differentiation. Importantly, alterations in expression levels or activation of components of the IGF network are implicated in many pathological conditions including diabetes, obesity and cancer initiation and progression. In this review we will initially cover some general aspects of IGF action and regulation in cancer and then focus in particular on the role of transcriptional regulators and novel interacting proteins, which functionally contribute in fine tuning IGF1R signaling in several cancer models. A deeper understanding of the biological relevance of this network of IGF1R modulators might provide novel therapeutic opportunities to block this system in neoplasia.
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Brčić I, Argyropoulos A, Liegl-Atzwanger B. Update on Molecular Genetics of Gastrointestinal Stromal Tumors. Diagnostics (Basel) 2021; 11:194. [PMID: 33525726 PMCID: PMC7912114 DOI: 10.3390/diagnostics11020194] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/21/2021] [Accepted: 01/23/2021] [Indexed: 12/14/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. The majority are sporadic, solitary tumors that harbor mutually exclusive KIT or PDGFRA gain-of-function mutations. The type of mutation in addition to risk stratification corresponds to the biological behavior of GIST and response to treatment. Up to 85% of pediatric GISTs and 10-15% of adult GISTs are devoid of these (KIT/PDGFRA) mutations and are referred to as wild-type GISTs (wt-GIST). It has been shown that these wt-GISTs are a heterogeneous tumor group with regard to their clinical behavior and molecular profile. Recent advances in molecular pathology helped to further sub-classify the so-called "wt-GISTs". Based on their significant clinical and molecular heterogeneity, wt-GISTs are divided into a syndromic and a non-syndromic (sporadic) subgroup. Recently, the use of succinate dehydrogenase B (SDHB) by immunohistochemistry has been used to stratify GIST into an SDHB-retained and an SDHB-deficient group. In this review, we focus on GIST sub-classification based on clinicopathologic, and molecular findings and discuss the known and yet emerging prognostic and predictive genetic alterations. We also give insights into the limitations of targeted therapy and highlight the mechanisms of secondary resistance.
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Affiliation(s)
| | | | - Bernadette Liegl-Atzwanger
- Diagnostic and Research Institute of Pathology, Medical University of Graz, 8010 Graz, Austria; (I.B.); (A.A.)
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15
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Ye S, Sharipova D, Kozinova M, Klug L, D'Souza J, Belinsky MG, Johnson KJ, Einarson MB, Devarajan K, Zhou Y, Litwin S, Heinrich MC, DeMatteo R, von Mehren M, Duncan JS, Rink L. Identification of Wee1 as a target in combination with avapritinib for gastrointestinal stromal tumor treatment. JCI Insight 2021; 6:143474. [PMID: 33320833 PMCID: PMC7934848 DOI: 10.1172/jci.insight.143474] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Accepted: 12/09/2020] [Indexed: 12/12/2022] Open
Abstract
Management of gastrointestinal stromal tumors (GISTs) has been revolutionized by the identification of activating mutations in KIT and PDGFRA and clinical application of RTK inhibitors in advanced disease. Stratification of GISTs into molecularly defined subsets provides insight into clinical behavior and response to approved targeted therapies. Although these RTK inhibitors are effective in most GISTs, resistance remains a significant clinical problem. Development of effective treatment strategies for refractory GISTs requires identification of novel targets to provide additional therapeutic options. Global kinome profiling has the potential to identify critical signaling networks and reveal protein kinases essential in GISTs. Using multiplexed inhibitor beads and mass spectrometry, we explored the majority of the kinome in GIST specimens from the 3 most common molecular subtypes (KIT mutant, PDGFRA mutant, and succinate dehydrogenase deficient) to identify kinase targets. Kinome profiling with loss-of-function assays identified an important role for G2/M tyrosine kinase, Wee1, in GIST cell survival. In vitro and in vivo studies revealed significant efficacy of MK-1775 (Wee1 inhibitor) in combination with avapritinib in KIT mutant and PDGFRA mutant GIST cell lines as well as notable efficacy of MK-1775 as a monotherapy in the engineered PDGFRA mutant line. These studies provide strong preclinical justification for the use of MK-1775 in GIST.
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Affiliation(s)
- Shuai Ye
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
| | - Dinara Sharipova
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
| | - Marya Kozinova
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.,Pirogov Russian National Research Medical University, Moscow, Russia
| | - Lilli Klug
- Portland VA Health Care System and OHSU Knight Cancer Institute, Portland, Oregon, USA
| | - Jimson D'Souza
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
| | - Martin G Belinsky
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
| | | | - Margret B Einarson
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
| | - Karthik Devarajan
- Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
| | - Yan Zhou
- Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
| | - Samuel Litwin
- Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
| | - Michael C Heinrich
- Portland VA Health Care System and OHSU Knight Cancer Institute, Portland, Oregon, USA
| | - Ronald DeMatteo
- Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Margaret von Mehren
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
| | | | - Lori Rink
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
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Rojas-Rodriguez R, Ziegler R, DeSouza T, Majid S, Madore AS, Amir N, Pace VA, Nachreiner D, Alfego D, Mathew J, Leung K, Moore Simas TA, Corvera S. PAPPA-mediated adipose tissue remodeling mitigates insulin resistance and protects against gestational diabetes in mice and humans. Sci Transl Med 2020; 12:eaay4145. [PMID: 33239385 PMCID: PMC8375243 DOI: 10.1126/scitranslmed.aay4145] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 04/25/2020] [Accepted: 10/21/2020] [Indexed: 12/11/2022]
Abstract
Pregnancy is a physiological state of continuous adaptation to changing maternal and fetal nutritional needs, including a reduction of maternal insulin sensitivity allowing for appropriately enhanced glucose availability to the fetus. However, excessive insulin resistance in conjunction with insufficient insulin secretion results in gestational diabetes mellitus (GDM), greatly increasing the risk for pregnancy complications and predisposing both mothers and offspring to future metabolic disease. Here, we report a signaling pathway connecting pregnancy-associated plasma protein A (PAPPA) with adipose tissue expansion in pregnancy. Adipose tissue plays a central role in the regulation of insulin sensitivity, and we show that, in both mice and humans, pregnancy caused remodeling of adipose tissue evidenced by altered adipocyte size, vascularization, and in vitro expansion capacity. PAPPA is known to be a metalloprotease secreted by human placenta that modulates insulin-like growth factor (IGF) bioavailability through prolteolysis of IGF binding proteins (IGFBPs) 2, 4, and 5. We demonstrate that recombinant PAPPA can stimulate ex vivo human adipose tissue expansion in an IGFBP-5- and IGF-1-dependent manner. Moreover, mice lacking PAPPA displayed impaired adipose tissue remodeling, pregnancy-induced insulin resistance, and hepatic steatosis, recapitulating multiple aspects of human GDM. In a cohort of 6361 pregnant women, concentrations of circulating PAPPA are inversely correlated with glycemia and odds of developing GDM. These data identify PAPPA and the IGF signaling pathway as necessary for the regulation of maternal adipose tissue physiology and systemic glucose homeostasis, with consequences for long-term metabolic risk and potential for therapeutic use.
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Affiliation(s)
- Raziel Rojas-Rodriguez
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
- Graduate School of Biomedical Sciences, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Rachel Ziegler
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Tiffany DeSouza
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Sana Majid
- Clinical Translational Research Pathway, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Aylin S Madore
- Departments of Obstetrics and Gynecology, University of Massachusetts Medical School and UMass Memorial Healthcare, Worcester, MA 01605, USA
| | - Nili Amir
- Departments of Obstetrics and Gynecology, University of Massachusetts Medical School and UMass Memorial Healthcare, Worcester, MA 01605, USA
| | - Veronica A Pace
- Clinical Translational Research Pathway, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Daniel Nachreiner
- Clinical Translational Research Pathway, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - David Alfego
- Division of Data Sciences and Technology, IT, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Jomol Mathew
- Division of Data Sciences and Technology, IT, University of Massachusetts Medical School, Worcester, MA 01605, USA
- Department of Population and Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA 01605, USA
| | - Katherine Leung
- Departments of Obstetrics and Gynecology, University of Massachusetts Medical School and UMass Memorial Healthcare, Worcester, MA 01605, USA
| | - Tiffany A Moore Simas
- Departments of Obstetrics and Gynecology, University of Massachusetts Medical School and UMass Memorial Healthcare, Worcester, MA 01605, USA
| | - Silvia Corvera
- Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
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Ethyl-2-amino-pyrrole-3-carboxylates are active against imatinib-resistant gastrointestinal stromal tumors in vitro and in vivo. Anticancer Drugs 2020; 30:475-484. [PMID: 30986804 DOI: 10.1097/cad.0000000000000753] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
We showed recently that ethyl-2-amino-pyrrole-3-carboxylates (EAPCs) exhibit potent antiproliferative activities against a broad spectrum of soft tissue sarcoma and gastrointestinal stromal tumor (GIST) cell lines in vitro. The molecular mechanism of action was owing to inhibition of tubulin polymerization and induction of a robust G2/M cell-cycle arrest, leading to the accumulation of tumor cells in the M-phase and induction of apoptosis. Given that more than 50% of the patients with GISTs develop resistance to imatinib (IM) over the 2 years of IM-based therapy, we examined whether EAPCs exhibit activity against IM-resistant GISTs in vitro and in vivo. A real-time antiproliferation assay illustrated the potent antiproliferative activities of EAPCs against IM-sensitive and IM-resistant GISTs. This was in agreement with the colony formation assay, which revealed potent antiproliferative activities of EAPCs against IM-resistant GISTs, being much stronger when compared with IM and doxorubicin, a topoisomerase II inhibitor. Next, we tested the efficacy of EAPCs in the xenograft model of GISTs, exhibiting secondary IM resistance owing to RTK switch (loss of c-KIT/gain of FGFR2α). A total of 30 5- to 8-week-old female nu/nu mice were subcutaneously inoculated into the flank areas with IM-resistant GIST-T1-R cells (100 μl of 1×10 GIST T-1R cells/ml suspension, in Dulbecco's PBS). Mice were randomized as control (untreated), IM (50 mg/kg), EAPC-20 (10 mg/kg) or EAPC-24 (10 mg/kg) and were treated orally for 10 days. IM has a minor inhibitory effect on tumor size, thus revealing GIST resistance to IM. In contrast, both of EAPCs effectively reduced the tumor size. This was associated with an increased intratumoral apoptosis as detected by immunohistochemical staining for cleaved caspase-3 on day 5 of the treatment. Furthermore, both EAPCs significantly reduced the proliferative activity of tumor cells in the central zones of tumors as measured by positivity for Ki-67 staining. More importantly, in EAPC-24-treated GISTs, the histological response was mainly characterized by the induction of necrosis, whereas EAPC-20 induced the signs of intratumoral fibrosis and myxoid degeneration. Collectively, our data suggest that EAPC-20 and EAPC-24 are the perspective antitumor agents that exhibit antiproliferative and cytotoxic activity against GISTs exhibiting secondary resistance to IM.
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Inhibition of FGF2-Mediated Signaling in GIST-Promising Approach for Overcoming Resistance to Imatinib. Cancers (Basel) 2020; 12:cancers12061674. [PMID: 32599808 PMCID: PMC7352302 DOI: 10.3390/cancers12061674] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 06/12/2020] [Accepted: 06/18/2020] [Indexed: 12/19/2022] Open
Abstract
Inhibition of KIT-signaling is a major molecular target for gastrointestinal stromal tumor (GIST) therapy, and imatinib mesylate (IM) is known as the most effective first-line treatment option for patients with advanced, unresectable, and/or metastatic GISTs. We show here for the first time that the inhibition of KIT-signaling in GISTs induces profound changes in the cellular secretome, leading to the release of multiple chemokines, including FGF-2. IM increased migration, invasion, and colony formation of IM-resistant GISTs in an FGF2-dependent manner, whereas the use of blocking anti-FGF2 antibodies or BGJ398, a selective FGFR inhibitor, abolished these effects, thus suggesting that the activation of FGF2-mediated signaling could serve as a compensatory mechanism of KIT-signaling inhibited in GISTs. Conversely, FGF-2 rescued the growth of IM-naive GISTs treated by IM and protected them from IM-induced apoptosis, consistent with the possible involvement of FGF-2 in tumor response to IM-based therapy. Indeed, increased FGF-2 levels in serum and tumor specimens were found in IM-treated mice bearing IM-resistant GIST xenografts, whereas BGJ398 used in combination with IM effectively inhibited their growth. Similarly, increased FGF-2 expression in tumor specimens from IM-treated patients revealed the activation of FGF2-signaling in GISTs in vivo. Collectively, the continuation of IM-based therapy for IM-resistant GISTs might facilitate disease progression by promoting the malignant behavior of tumors in an FGF2-dependent manner. This provides a rationale to evaluate the effectiveness of the inhibitors of FGF-signaling for IM-resistant GISTs.
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von Mehren M, George S, Heinrich MC, Schuetze SM, Yap JT, Yu JQ, Abbott A, Litwin S, Crowley J, Belinsky M, Janeway KA, Hornick JL, Flieder DB, Chugh R, Rink L, Van den Abbeele AD. Linsitinib (OSI-906) for the Treatment of Adult and Pediatric Wild-Type Gastrointestinal Stromal Tumors, a SARC Phase II Study. Clin Cancer Res 2020; 26:1837-1845. [PMID: 31792037 PMCID: PMC7856429 DOI: 10.1158/1078-0432.ccr-19-1069] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 07/03/2019] [Accepted: 11/22/2019] [Indexed: 12/21/2022]
Abstract
PURPOSE Most gastrointestinal stromal tumors (GIST) have activating mutations of KIT, PDGFRA, or uncommonly BRAF. Fifteen percent of adult and 85% of pediatric GISTs are wild type (WT), commonly having high expression of IGF-1R and loss of succinate dehydrogenase (SDH) complex function. We tested the efficacy of linsitinib, an oral TKI IGF-1R inhibitor, in patients with WT GIST. PATIENTS AND METHODS A multicenter phase II trial of linsitinib was conducted. The primary endpoint was objective response rate. Secondary endpoints were clinical benefit rate: complete response, partial response, and stable disease (SD) ≥ 9 months, and quantitative 2[18F]fluoro-2-deoxy-D-glucose (FDG) metabolic response (MR) at week 8. Serum levels for glucose, insulin, IGF-1R ligand IGF1, and binding proteins were obtained to explore correlations to patient outcomes and FDG-PET results. RESULTS Twenty patients were accrued in a 6-month period. Grade 3-4 toxicities possibly related to linsitinib were uncommon (8.5%). No objective responses were seen. Clinical benefit rate (CBR) at 9 months was 40%. Intense FDG uptake was observed at baseline, with partial MR of 12% and stable metabolic disease of 65% at week 8; these patients had RECIST 1.1 SD as their best response. Progression-free survival (PFS) and overall survival Kaplan-Meier estimates at 9 months were 52% and 80%, respectively. SDHA/B loss determined by IHC was seen in 35% and 88% of cases, respectively. CONCLUSIONS Linsitinib is well tolerated in patients with WT GIST. Although the 9-month CBR was 40%, and PFS at 9 months was 52%, no objective responses were observed. Rapid accrual to this study demonstrates that clinical trials of experimental agents in selected subtypes of GIST are feasible.
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Affiliation(s)
| | | | - Michael C Heinrich
- Portland VA Health Care System and OHSU Knight Cancer Institute, Portland, Oregon
| | | | - Jeffrey T Yap
- Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
| | - Jain Q Yu
- Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | | | | | - John Crowley
- Cancer Research and Biostatistics, Seattle, Washington
| | | | | | - Jason L Hornick
- Harvard Medical School, Boston, Massachusetts
- Brigham Health, Boston, Massachusetts
| | | | - Rashmi Chugh
- University of Michigan, Ann Arbor, Michigan
- Sarcoma Alliance for Research through Collaboration, Ann Arbor, Michigan
| | - Lori Rink
- Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | - Annick D Van den Abbeele
- Dana-Farber Cancer Institute, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
- Brigham Health, Boston, Massachusetts
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Liu P, Tan F, Liu H, Li B, Lei T, Zhao X. The Use of Molecular Subtypes for Precision Therapy of Recurrent and Metastatic Gastrointestinal Stromal Tumor. Onco Targets Ther 2020; 13:2433-2447. [PMID: 32273716 PMCID: PMC7102917 DOI: 10.2147/ott.s241331] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 03/10/2020] [Indexed: 12/19/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor in the digestive tract. Tyrosine kinase inhibitors (TKIs), represented by imatinib, sunitinib, and regorafenib, have become the main treatment for recurrent and metastatic GISTs. With the wide application of mutation analysis and the precision medicine, molecular characteristics have been determined that not only predict the prognosis of patients with recurrent and metastatic GISTs, but also are closely related to the efficacy of first-, second- and third-line TKIs for GISTs, as well as other TKIs. Despite the significant effects of TKIs, the emergence of primary and secondary resistance ultimately leads to treatment failure and tumor progression. Currently, due to the signal transmission of KIT/PDGFRA during onset and tumor progression, strategies to counteract drug resistance include the replacement of TKIs and the development of new drugs that are directed towards carcinogenic mutations. In addition, it is also the embodiment of precision medicine for GISTs to explore new carcinogenic mechanisms and develop new drugs relying on new biotechnology. Surgery can benefit specific patients but its major purpose is to diminish the resistant clones. However, the prognosis of recurrent and metastatic patients is still unsatisfactory. Therefore, it is worth paying attention to how to maximize the benefits for patients.
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Affiliation(s)
- Peng Liu
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan410008, People’s Republic of China
| | - Fengbo Tan
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan410008, People’s Republic of China
| | - Heli Liu
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan410008, People’s Republic of China
| | - Bin Li
- Department of Oncology, Xiangya Hospital, Central South University, Changsha410008, Hunan, People’s Republic of China
| | - Tianxiang Lei
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan410008, People’s Republic of China
| | - Xianhui Zhao
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan410008, People’s Republic of China
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21
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Zhu G, Shi J, Zhang S, Guo Y, Huang L, Zhao H, Jiang Y, Sun J. Loss of PI3 kinase association improves the sensitivity of secondary mutation of KIT to Imatinib. Cell Biosci 2020; 10:16. [PMID: 32082541 PMCID: PMC7017564 DOI: 10.1186/s13578-020-0377-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2019] [Accepted: 01/16/2020] [Indexed: 12/13/2022] Open
Abstract
Background KIT mutations are the predominant driver mutations in gastrointestinal stromal tumors (GISTs), and targeted therapy against KIT has improved treatment outcome dramatically. However, gaining secondary mutation of KIT confers drug resistance of GISTs leading to treatment failure. Results In this study, we found that secondary mutation of KIT dramatically increases the ligand-independent activation of the receptor and their resistance to the often used KIT inhibitor Imatinib in the treatment of GISTs. PI3 kinase plays essential roles in the cell transformation mediated by the primary mutation of KIT. We found that loss of PI3 kinase association, but not the inhibition of the lipid kinase activity of PI3 kinase, inhibits the ligand-independent activation of secondary mutations of KIT, and increases their sensitivity to Imatinib, and loss of PI3 kinase association inhibits secondary mutations of KIT mediated cell survival and proliferation in vitro. The in vivo assay further showed that the growth of tumors carrying secondary mutations of KIT is more sensitive to Imatinib when PI3 kinase association is blocked while inhibition of the lipid kinase activity of PI3 kinase cannot inhibit tumor growth, indicating that PI3 kinase is important for the drug resistance of secondary mutation of KIT independent of the lipid kinase activity of PI3 kinase. Conclusions Our results suggested that PI3 kinase is necessary for the ligand-independent activation of secondary mutations of KIT, and loss of PI3 kinase association improves the sensitivity of secondary mutations to the targeted therapy independent of the lipid kinase activity of PI3 kinase.
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Affiliation(s)
- Guangrong Zhu
- 1School of Basic Medical Sciences, Ningxia Medical University, No. 1160 Shengli Street, Yinchuan, 750004 China
| | - Jun Shi
- 1School of Basic Medical Sciences, Ningxia Medical University, No. 1160 Shengli Street, Yinchuan, 750004 China
| | - Shaoting Zhang
- 1School of Basic Medical Sciences, Ningxia Medical University, No. 1160 Shengli Street, Yinchuan, 750004 China
| | - Yue Guo
- 2Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Ling Huang
- 1School of Basic Medical Sciences, Ningxia Medical University, No. 1160 Shengli Street, Yinchuan, 750004 China
| | - Hui Zhao
- 2Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China.,3Kunming Institute of Zoology, Chinese Academy of Sciences-The Chinese University of Hong Kong Joint Laboratory of Bioresources and Molecular Research of Common Diseases, Hong Kong, Hong Kong SAR, China
| | - Yideng Jiang
- 1School of Basic Medical Sciences, Ningxia Medical University, No. 1160 Shengli Street, Yinchuan, 750004 China.,4NHC Key Laboratory of Metabolic Cardiovascular Diseases Research (Ningxia Medical University), Yinchuan, China.,Ningxia Key Laboratory of Vascular Injury and Repair Research, Yinchuan, China
| | - Jianmin Sun
- 1School of Basic Medical Sciences, Ningxia Medical University, No. 1160 Shengli Street, Yinchuan, 750004 China.,6Division of Translational Cancer Research, Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden
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22
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Osher E, Macaulay VM. Therapeutic Targeting of the IGF Axis. Cells 2019; 8:E895. [PMID: 31416218 PMCID: PMC6721736 DOI: 10.3390/cells8080895] [Citation(s) in RCA: 103] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 08/04/2019] [Accepted: 08/09/2019] [Indexed: 12/17/2022] Open
Abstract
The insulin like growth factor (IGF) axis plays a fundamental role in normal growth and development, and when deregulated makes an important contribution to disease. Here, we review the functions mediated by ligand-induced IGF axis activation, and discuss the evidence for the involvement of IGF signaling in the pathogenesis of cancer, endocrine disorders including acromegaly, diabetes and thyroid eye disease, skin diseases such as acne and psoriasis, and the frailty that accompanies aging. We discuss the use of IGF axis inhibitors, focusing on the different approaches that have been taken to develop effective and tolerable ways to block this important signaling pathway. We outline the advantages and disadvantages of each approach, and discuss progress in evaluating these agents, including factors that contributed to the failure of many of these novel therapeutics in early phase cancer trials. Finally, we summarize grounds for cautious optimism for ongoing and future studies of IGF blockade in cancer and non-malignant disorders including thyroid eye disease and aging.
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Affiliation(s)
- Eliot Osher
- Department of Oncology, University of Oxford, Oxford, OX3 7DQ, UK
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23
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Yan J, Chen D, Chen X, Sun X, Dong Q, Hu C, Zhou F, Chen W. Downregulation of lncRNA CCDC26 contributes to imatinib resistance in human gastrointestinal stromal tumors through IGF-1R upregulation. ACTA ACUST UNITED AC 2019; 52:e8399. [PMID: 31166382 PMCID: PMC6556970 DOI: 10.1590/1414-431x20198399] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 02/21/2019] [Indexed: 12/11/2022]
Abstract
Imatinib is the first line of therapy for patients with metastatic or gastrointestinal stromal tumors (GIST). However, drug resistance limits the long-term effect of imatinib. Long non-coding RNAs (lncRNAs) are emerging as key players in regulating drug resistance in cancer. In this study, we investigated the association between lncRNA CCDC26 and IGF-1R in GIST and their involvement in drug resistance. Considering the key role of lncRNAs in drug resistance in cancer, we hypothesized that IGF-1R is regulated by lncRNAs. The expression of a series of reported drug resistance-related lncRNAs, including CCDC26, ARF, H19, NBR2, NEAT1, and HOTAIR, in GIST cells treated with imatinib H19 was examined at various time-points by qRT-PCR. Based on our results and published literature, CCDC26, a strongly down-regulated lncRNA following imatinib treatment, was chosen as our research target. GIST cells with high expression of CCDC26 were sensitive to imatinib treatment while knockdown of CCDC26 significantly increased the resistance to imatinib. Furthermore, we found that CCDC26 interacted with c-KIT by RNA pull down, and that CCDC26 knockdown up-regulated the expression of IGF-1R. Moreover, IGF-1R inhibition reversed CCDC26 knockdown-mediated imatinib resistance in GIST. These results indicated that treatments targeting CCDC26-IGF-1R axis would be useful in increasing sensitivity to imatinib in GIST.
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Affiliation(s)
- Jingyi Yan
- Department of Gastroenterology and General Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Didi Chen
- Department of Radiotherapy and Medical Oncology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Xiaolei Chen
- Department of Gastroenterology and General Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Xuecheng Sun
- Department of Gastroenterology and Hepatology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Qiantong Dong
- Department of Gastroenterology and General Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Changyuan Hu
- Department of Gastroenterology and General Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Feng Zhou
- Department of Gastroenterology and General Surgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Wei Chen
- Tongde Hospital of Zhejiang Province, Hangzhou, Zhejiang Province, China
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24
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Inhibition of fibroblast growth factor receptor-signaling sensitizes imatinib-resistant gastrointestinal stromal tumors to low doses of topoisomerase II inhibitors. Anticancer Drugs 2019; 29:549-559. [PMID: 29697413 DOI: 10.1097/cad.0000000000000637] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The acquired resistance of gastrointestinal stromal tumors (GISTs) to the targeted-based therapy remains the driving force to identify the novel approaches that are capable of increasing the sensitivity of GISTs to the current therapeutic regimens. Our present data show that BGJ398, a selective fibroblast growth factor receptor (FGFR) inhibitor, sensitizes imatinib (IM)-resistant GIST cells with receptor tyrosine kinase (RTK) switch (loss of c-KIT/gain of pFGFR2a) to the low doses of topoisomerase II inhibitors - doxorubicin (Dox) and etoposide (Eto). Mechanistically, pretreatment of IM-resistant GIST cells with BGJ398 for 12 h markedly enhanced proapoptotic and growth-suppressive effects of Dox (or Eto). Indeed, a significant cleavage of PARP and caspase-3 was observed in GIST cells treated with a combination of FGFR and topoisomerase II inhibitor. In contrast, no signs of apoptosis were detected in IM-resistant GIST cells treated with BGJ398, whereas the low doses of Dox (Eto) exerted the minor proapoptotic effects on GISTs. The mechanism of BGJ398-induced sensitization of GIST to topoisomerase II inhibitors might be because of attenuation of DNA damage signaling and repair. Indeed, we observed a marked decrease in Rad51 expression in GIST cells treated with BGJ398 together with Dox. Similar results were obtained when an overexpressed pFGFR2a was knocked down by corresponding siRNA before Dox (Eto) exposure. Moreover, FGFR inhibition/depletion caused a loss of Rad51 foci in Dox-treated GIST cells, suggesting that FGFR-signaling plays an important regulatory role in homology-mediated DNA repair. Our data show that combined therapy (RTKs inhibitors supplemented with low doses of topoisomerase II inhibitors) might be effective for unresectable and metastatic forms of GISTs. In case of resistance to IM because of RTKs switch indicated above, FGFR inhibitors (e.g. BGJ398) might be potentially useful because of their ability to sensitize tumor cells to topoisomerase II inhibitors and induce tumor cell apoptosis by targeting DNA double-strand breaks repair.
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25
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Carmagnani Pestana R, Groisberg R, Roszik J, Subbiah V. Precision Oncology in Sarcomas: Divide and Conquer. JCO Precis Oncol 2019; 3:PO.18.00247. [PMID: 32914012 PMCID: PMC7446356 DOI: 10.1200/po.18.00247] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/11/2019] [Indexed: 12/18/2022] Open
Abstract
Sarcomas are a heterogeneous group of rare malignancies that exhibit remarkable heterogeneity, with more than 50 subtypes recognized. Advances in next-generation sequencing technology have resulted in the discovery of genetic events in these mesenchymal tumors, which in addition to enhancing understanding of the biology, have opened up avenues for molecularly targeted therapy and immunotherapy. This review focuses on how incorporation of next-generation sequencing has affected drug development in sarcomas and strategies for optimizing precision oncology for these rare cancers. In a significant percentage of soft tissue sarcomas, which represent up to 40% of all sarcomas, specific driver molecular abnormalities have been identified. The challenge to evaluate these mutations across rare cancer subtypes requires the careful characterization of these genetic alterations to further define compelling drivers with therapeutic implications. Novel models of clinical trial design also are needed. This shift would entail sustained efforts by the sarcoma community to move from one-size-fits-all trials, in which all sarcomas are treated similarly, to divide-and-conquer subtype-specific strategies.
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Affiliation(s)
| | - Roman Groisberg
- The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Jason Roszik
- The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Vivek Subbiah
- The University of Texas MD Anderson Cancer Center, Houston, TX
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26
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Kays JK, Sohn JD, Kim BJ, Goze K, Koniaris LG. Approach to wild-type gastrointestinal stromal tumors. Transl Gastroenterol Hepatol 2018; 3:92. [PMID: 30603728 DOI: 10.21037/tgh.2018.10.13] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Accepted: 10/29/2018] [Indexed: 12/24/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) arise from the intestinal pacemaker cells of Cajal. Wild-type gastrointestinal stromal tumors (WT-GIST) are a unique and uncommon subtype of GISTs that lack activating mutations in the tyrosine kinase c-KIT or platelet derived growth factor receptor alpha (PDGFRA) receptors. The lack of these growth-stimulating mutations renders tyrosine kinase receptor inhibitors, such as imatinib mesylate, relatively ineffective against these tumors. WT-GIST arises most commonly due to underlying alternate proliferative signals associated with germ-line, genetic mutations. WT-GIST frequently arises in patients with BRAF mutations, Carney's Triad or neurofibromatosis type-1 (NF-1). All patients with WT-GIST require a careful examination for germ-line mutations and very close observation for recurrent tumors. Surgery remains a mainstay therapy for these patients. This review aims to discuss the most recent data available on the diagnosis and treatment of WT-GIST.
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Affiliation(s)
- Joshua K Kays
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jeffrey D Sohn
- Monmouth Medical Center, Robert Wood Johnson Barnabas Health, Long Branch, NJ, USA
| | - Bradford J Kim
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Katherine Goze
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Leonidas G Koniaris
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
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27
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Receptor Tyrosine Kinase-Targeted Cancer Therapy. Int J Mol Sci 2018; 19:ijms19113491. [PMID: 30404198 PMCID: PMC6274851 DOI: 10.3390/ijms19113491] [Citation(s) in RCA: 184] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 10/22/2018] [Accepted: 11/02/2018] [Indexed: 12/14/2022] Open
Abstract
In the past two decades, several molecular targeted inhibitors have been developed and evaluated clinically to improve the survival of patients with cancer. Molecular targeted inhibitors inhibit the activities of pathogenic tyrosine kinases. Particularly, aberrant receptor tyrosine kinase (RTK) activation is a potential therapeutic target. An increased understanding of genetics, cellular biology and structural biology has led to the development of numerous important therapeutics. Pathogenic RTK mutations, deletions, translocations and amplification/over-expressions have been identified and are currently being examined for their roles in cancers. Therapies targeting RTKs are categorized as small-molecule inhibitors and monoclonal antibodies. Studies are underway to explore abnormalities in 20 types of RTK subfamilies in patients with cancer or other diseases. In this review, we describe representative RTKs important for developing cancer therapeutics and predicting or evaluated resistance mechanisms.
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28
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Wang WJ, Li HT, Yu JP, Li YM, Han XP, Chen P, Yu WW, Chen WK, Jiao ZY, Liu HB. Identification of key genes and associated pathways in KIT/PDGFRA wild‑type gastrointestinal stromal tumors through bioinformatics analysis. Mol Med Rep 2018; 18:4499-4515. [PMID: 30221743 PMCID: PMC6172374 DOI: 10.3892/mmr.2018.9457] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2018] [Accepted: 08/23/2018] [Indexed: 12/20/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common type of mesenchymal tumor in the gastrointestinal tract. The present study aimed to identify the potential candidate biomarkers that may be involved in the pathogenesis and progression of v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT)/platelet-derived growth factor receptor α (PDGFRA) wild-type GISTs. A joint bioinformatics analysis was performed to identify the differentially expressed genes (DEGs) in wild-type GIST samples compared with KIT/PDGFRA mutant GIST samples. Gene Ontology function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of DEGs was conducted using Database for Annotation, Visualization and Integrated Discovery and KEGG Orthology-Based Annotation System (KOBAS) online tools, respectively. Protein-protein interaction (PPI) networks of the DEGs were constructed using Search Tool for the Retrieval of Interacting Genes online tool and Cytoscape, and divided into sub-networks using the Molecular Complex Detection (MCODE) plug-in. Furthermore, enrichment analysis of DEGs in the modules was analyzed with KOBAS. In total, 546 DEGs were identified, including 238 upregulated genes primarily enriched in ‘cell adhesion’, ‘biological adhesion’, ‘cell-cell signaling’, ‘PI3K-Akt signaling pathway’ and ‘ECM-receptor interaction’, while the 308 downregulated genes were predominantly involved in ‘inflammatory response’, ‘sterol metabolic process’ and ‘fatty acid metabolic process’, ‘small GTPase mediated signal transduction’, ‘cAMP signaling pathway’ and ‘proteoglycans in cancer’. A total of 25 hub genes were obtained and four modules were mined from the PPI network, and sub-networks also revealed these genes were primarily involved in significant pathways, including ‘PI3K-Akt signaling pathway’, ‘proteoglycans in cancer’, ‘pathways in cancer’, ‘Rap1 signaling pathway’, ‘ECM-receptor interaction’, ‘phospholipase D signaling pathway’, ‘ras signaling pathway’ and ‘cGMP-PKG signaling pathway’. These results suggested that several key hub DEGs may serve as potential candidate biomarkers for wild-type GISTs, including phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit γ, insulin like growth factor 1 receptor, hepatocyte growth factor, thrombospondin 1, Erb-B2 receptor tyrosine kinase 2 and matrix metallopeptidase 2. However, further experiments are required to confirm these results.
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Affiliation(s)
- Wen-Jie Wang
- Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu 730030, P.R. China
| | - Hong-Tao Li
- Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu 730030, P.R. China
| | - Jian-Ping Yu
- Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu 730030, P.R. China
| | - Yu-Min Li
- Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu 730030, P.R. China
| | - Xiao-Peng Han
- Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu 730030, P.R. China
| | - Peng Chen
- Department of General Surgery, Lanzhou General Hospital of Chinese People's Liberation Army, Lanzhou, Gansu 730050, P.R. China
| | - Wen-Wen Yu
- Department of General Surgery, Lanzhou General Hospital of Chinese People's Liberation Army, Lanzhou, Gansu 730050, P.R. China
| | - Wei-Kai Chen
- Department of General Surgery, Lanzhou General Hospital of Chinese People's Liberation Army, Lanzhou, Gansu 730050, P.R. China
| | - Zuo-Yi Jiao
- Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu 730030, P.R. China
| | - Hong-Bin Liu
- Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu 730030, P.R. China
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29
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Liu X, Chu KM. Molecular biomarkers for prognosis of gastrointestinal stromal tumor. Clin Transl Oncol 2018; 21:145-151. [PMID: 30003531 DOI: 10.1007/s12094-018-1914-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 06/25/2018] [Indexed: 12/13/2022]
Abstract
Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the gastrointestinal tract. However, the development of molecular markers, especially circulating biomarkers, remains largely undone for the prognosis of GIST. We discussed the clinical-pathological characteristics of GIST and identified potential biomarkers for guidance of therapy and prognosis of GIST. Around 90% of GISTs contain mutations in KIT or PDGFRA and the remaining 10% of GISTs are wild-type. Recent studies have indicated that various DNAs and miRNAs could serve as potential biomarkers for prognosis of GIST, including KIT, PDGFRA, other DNAs (such as BRAF, SDH, SETD2 and ROR2), and microRNAs (miRNAs). The pressing need and challenges in the development of circulating prognostic biomarkers for GIST are also discussed. Although challenges remain, DNAs and miRNAs are promising circulating biomarkers for surveillance and prognosis of GIST. Advances in clarification of aberrant molecular alterations may open new avenues for exploration of reliable and robust biomarkers to improve the management of GIST.
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Affiliation(s)
- X Liu
- Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong.
| | - K-M Chu
- Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong. .,Department of Surgery, Queen Mary Hospital, Pokfulam, Hong Kong.
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30
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Mancarella C, Scotlandi K. IGF system in sarcomas: a crucial pathway with many unknowns to exploit for therapy. J Mol Endocrinol 2018; 61:T45-T60. [PMID: 29273680 DOI: 10.1530/jme-17-0250] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Accepted: 12/22/2017] [Indexed: 12/22/2022]
Abstract
The insulin-like growth factor (IGF) system has gained substantial interest due to its involvement in regulating cell proliferation, differentiation and survival during anoikis and after conventional and targeted therapies. However, results from clinical trials have been largely disappointing, with only a few but notable exceptions, such as trials targeting sarcomas, especially Ewing sarcoma. This review highlights key studies focusing on IGF signaling in sarcomas, specifically studies underscoring the properties that make this system an attractive therapeutic target and identifies new relationships that may be exploited. This review discusses the potential roles of IGF2 mRNA-binding proteins (IGF2BPs), discoidin domain receptors (DDRs) and metalloproteinase pregnancy-associated plasma protein-A (PAPP-A) in regulating the IGF system. Deeper investigation of these novel regulators of the IGF system may help us to further elucidate the spatial and temporal control of the IGF axis, as understanding the control of this axis is essential for future clinical studies.
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Affiliation(s)
- Caterina Mancarella
- Experimental Oncology Lab, CRS Development of Biomolecular Therapies, Orthopaedic Rizzoli Institute, Bologna, Italy
| | - Katia Scotlandi
- Experimental Oncology Lab, CRS Development of Biomolecular Therapies, Orthopaedic Rizzoli Institute, Bologna, Italy
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31
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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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Vishwamitra D, George SK, Shi P, Kaseb AO, Amin HM. Type I insulin-like growth factor receptor signaling in hematological malignancies. Oncotarget 2018; 8:1814-1844. [PMID: 27661006 PMCID: PMC5352101 DOI: 10.18632/oncotarget.12123] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Accepted: 09/12/2016] [Indexed: 12/19/2022] Open
Abstract
The insulin-like growth factor (IGF) signaling system plays key roles in the establishment and progression of different types of cancer. In agreement with this idea, substantial evidence has shown that the type I IGF receptor (IGF-IR) and its primary ligand IGF-I are important for maintaining the survival of malignant cells of hematopoietic origin. In this review, we discuss current understanding of the role of IGF-IR signaling in cancer with a focus on the hematological neoplasms. We also address the emergence of IGF-IR as a potential therapeutic target for the treatment of different types of cancer including plasma cell myeloma, leukemia, and lymphoma.
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Affiliation(s)
- Deeksha Vishwamitra
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Suraj Konnath George
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ping Shi
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
| | - Ahmed O Kaseb
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hesham M Amin
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA
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33
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Kumar AS, Rayala SK, Venkatraman G. Targeting IGF1R pathway in cancer with microRNAs: How close are we? RNA Biol 2018; 15:320-326. [PMID: 28613101 DOI: 10.1080/15476286.2017.1338240] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Cancer of the head and neck are the most common cancers in India and account for 30% of all cancers. At molecular level, it could be attributed to the overexpression of growth factors like IGF1-R, EGFR, VEGF-R and deregulation of cell cycle regulators and tumor suppressors. IGF1-R is an emerging target in head and neck cancer treatment, because of its reported role in tumor development, progression and metastasis. IGF1R targeted agents are in advanced stages of clinical development. Nevertheless, these agents suffer from several disadvantages including acquired resistance and toxic side effects. Hence there is a need for developing newer agents targeting not only the receptor but also its downstream signaling. miRNAs are considered as master regulators of gene expression of multiple genes and has been widely reported to be a promising therapeutic strategy. This review discusses the present status of research in both these arenas and emphasizes the role of miRNA as a promising agent for biologic therapy.
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Affiliation(s)
- Arathy S Kumar
- a Department of Biotechnology , Indian Institute of Technology, Madras (IIT M) , Chennai , India
| | - Suresh K Rayala
- a Department of Biotechnology , Indian Institute of Technology, Madras (IIT M) , Chennai , India
| | - Ganesh Venkatraman
- b Department of Human Genetics , College of Biomedical Sciences, Technology & Research, Sri Ramachandra University , Porur, Chennai , India
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Kenny C, McDonagh N, Lazaro A, O'Meara E, Klinger R, O'Connor D, Roche F, Hokamp K, O'Sullivan MJ. Dysregulated mitogen-activated protein kinase signalling as an oncogenic basis for clear cell sarcoma of the kidney. J Pathol 2018; 244:334-345. [PMID: 29243812 DOI: 10.1002/path.5020] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Revised: 11/30/2017] [Accepted: 12/08/2017] [Indexed: 01/06/2023]
Abstract
The oncogenic mechanisms and tumour biology underpinning clear cell sarcoma of the kidney (CCSK), the second commonest paediatric renal malignancy, are poorly understood and currently, therapy depends heavily on doxorubicin with cardiotoxic side-effects. Previously, we characterized the balanced t(10;17)(q22;p13) chromosomal translocation, identified at that time as the only recurrent genetic aberration in CCSK. This translocation results in an in-frame fusion of the genes YWHAE (encoding 14-3-3ϵ) and NUTM2, with a somatic incidence of 12%. Clinico-pathological features of that cohort suggested that this aberration might be associated with higher stage and grade disease. Since no primary CCSK cell line exists, we generated various stably transfected cell lines containing doxycycline-inducible HA-tagged YWHAE-NUTM2, in order to study the effect of expressing this transcript. 14-3-3ϵ-NUTM2-expressing cells exhibited significantly greater cell migration compared to isogenic controls. Gene and protein expression studies were indicative of dysregulated MAPK/PI3K-AKT signalling, and by blocking these pathways using neutralizing antibodies, the migratory advantage conferred by the transcript was abrogated. Importantly, CCSK tumour samples similarly show up-regulation/activation of these pathways. These results support the oncogenic role of 14-3-3ϵ-NUTM2 in CCSK and provide avenues for the exploration of novel therapeutic approaches. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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MESH Headings
- 14-3-3 Proteins/genetics
- 14-3-3 Proteins/metabolism
- Animals
- Cell Movement
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Gene Expression Regulation, Enzymologic
- Gene Expression Regulation, Neoplastic
- Gene Fusion
- HEK293 Cells
- Humans
- Kidney Neoplasms/enzymology
- Kidney Neoplasms/genetics
- Kidney Neoplasms/pathology
- Mice
- Mitogen-Activated Protein Kinases/genetics
- Mitogen-Activated Protein Kinases/metabolism
- NIH 3T3 Cells
- Oncogene Proteins, Fusion/genetics
- Oncogene Proteins, Fusion/metabolism
- Phosphatidylinositol 3-Kinase/metabolism
- Proto-Oncogene Proteins c-akt/metabolism
- Sarcoma, Clear Cell/enzymology
- Sarcoma, Clear Cell/genetics
- Sarcoma, Clear Cell/pathology
- Signal Transduction
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Affiliation(s)
- Colin Kenny
- School of Medicine, University of Dublin, Trinity College, Dublin, Ireland
| | - Naomi McDonagh
- School of Medicine, University of Dublin, Trinity College, Dublin, Ireland
| | - Antonio Lazaro
- School of Medicine, University of Dublin, Trinity College, Dublin, Ireland
| | - Elaine O'Meara
- School of Medicine, University of Dublin, Trinity College, Dublin, Ireland
| | - Rut Klinger
- Conway Institute, University College Dublin, Belfield, Dublin, Ireland
| | - Darran O'Connor
- Conway Institute, University College Dublin, Belfield, Dublin, Ireland
| | - Fiona Roche
- School of Genetics and Microbiology, University of Dublin, Trinity College, Dublin, Ireland
| | - Karsten Hokamp
- School of Genetics and Microbiology, University of Dublin, Trinity College, Dublin, Ireland
| | - Maureen J O'Sullivan
- School of Medicine, University of Dublin, Trinity College, Dublin, Ireland
- Our Lady's Children's Hospital, Crumlin, Dublin, Ireland
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Niinuma T, Suzuki H, Sugai T. Molecular characterization and pathogenesis of gastrointestinal stromal tumor. Transl Gastroenterol Hepatol 2018; 3:2. [PMID: 29441367 DOI: 10.21037/tgh.2018.01.02] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Accepted: 01/04/2018] [Indexed: 12/11/2022] Open
Abstract
Most gastrointestinal stromal tumors (GISTs) harbor activating mutations in the receptor tyrosine kinase gene KIT or platelet-derived growth factor receptor alpha (PDGFRA), and the resultant activation of downstream signals plays a pivotal role in the development of GISTs. The sites of the tyrosine kinase gene mutations are associated with the biological behavior of GISTs, including risk category, clinical outcome and drug response. Mutations in RAS signaling pathway genes, including KRAS and BRAF, have also been reported in KIT/PDGFRA wild-type GISTs, though they are rare. Neurofibromin 1 (NF1) is a tumor suppressor gene mutated in neurofibromatosis type 1. Patients with NF1 mutations are at high risk of developing GISTs. Recent findings suggest that altered expression or mutation of members of succinate dehydrogenase (SDH) heterotetramer are causally associated with GIST development through induction of aberrant DNA methylation. At present, GISTs with no alterations in KIT, PDGFRA, RAS signaling genes or SDH family genes are referred to as true wild-type GISTs. KIT and PDGFRA mutations are thought as the earliest events in GIST development, and subsequent accumulation of chromosomal aberrations and other molecular alterations are required for malignant progression. In addition, recent studies have shown that epigenetic alterations and noncoding RNAs also play key roles in the pathogenesis of GISTs.
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Affiliation(s)
- Takeshi Niinuma
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hiromu Suzuki
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
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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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A Novel Receptor Tyrosine Kinase Switch Promotes Gastrointestinal Stromal Tumor Drug Resistance. Molecules 2017; 22:molecules22122152. [PMID: 29206199 PMCID: PMC6149963 DOI: 10.3390/molecules22122152] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 11/27/2017] [Accepted: 12/01/2017] [Indexed: 02/07/2023] Open
Abstract
The fact that most gastrointestinal stromal tumors (GISTs) acquire resistance to imatinib (IM)-based targeted therapy remains the main driving force to identify novel molecular targets that are capable to increase GISTs sensitivity to the current therapeutic regimens. Secondary resistance to IM in GISTs typically occurs due to several mechanisms that include hemi- or homo-zygous deletion of the wild-type KIT allele, overexpression of focal adhesion kinase (FAK) and insulin-like growth factor receptor I (IGF-1R) amplification, BRAF mutation, a RTK switch (loss of c-KIT and gain of c-MET/AXL), etc. We established and characterized the IM-resistant GIST T-1 cell line (GIST T-1R) lacking secondary c-KIT mutations typical for the IM-resistant phenotype. The resistance to IM in GIST T-1R cells was due to RTK switch (loss of c-KIT/gain of FGFR2α). Indeed, we have found that FGFR inhibition reduced cellular viability, induced apoptosis and affected the growth kinetics of the IM-resistant GISTs in vitro. In contrast, IM-naive GIST T-1 parental cells were not susceptible to FGFR inhibition. Importantly, inhibition of FGF-signaling restored the susceptibility to IM in IM-resistant GISTs. Additionally, IM-resistant GISTs were less susceptible to certain chemotherapeutic agents as compared to parental IM-sensitive GIST cells. The chemoresistance in GIST T-1R cells is not due to overexpression of ABC-related transporter proteins and might be the result of upregulation of DNA damage signaling and repair (DDR) genes involved in DNA double-strand break (DSB) repair pathways (e.g., XRCC3, Rad51, etc.). Taken together, the established GIST T-1R cell subline might be used for in vitro and in vivo studies to examine the efficacy and prospective use of FGFR inhibitors for patients with IM-resistant, un-resectable and metastatic forms of GISTs with the type of RTK switch indicated above.
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Vokuhl C, de Leon-Escapini L, Leuschner I. Strong Expression and Amplification of IGF1R in Pleuropulmonary Blastomas. Pediatr Dev Pathol 2017; 20:475-481. [PMID: 28382840 DOI: 10.1177/1093526617700945] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Pleuropulmonary blastoma (PPB) is a rare malignant intrathoracic tumor primarily affecting children under 5 years of age. PPBs are histologically divided into 3 subtypes: Type 1 PPBs are composed of multiple cysts, and type 3 is a solid lesion with a variable morphologic appearance. Type 2 has a mixed morphology consisting of cystic and solid areas. The genetics of PPB are poorly understood. We analyzed 16 cases of the Kiel Paediatric Tumor Registry with the diagnosis of PPB by comparative genomic hybridization and confirmed some genetic changes by fluorescence in situ hybridization. Furthermore, we performed immunohistochemistry to evaluate insulin-like growth factor type 1 (IGF1R) protein expression. Frequent findings by comparative genomic hybridization were losses on 4q, 5q, 9p and gains on chromosome 8, 17, and 20q. Genomic amplification was observed in 5 cases, 4 related to 15q25qter and 1 to 1p. Fluorescence in situ hybridization could confirm 7 gains of chromosome 8 (7/16, 44%) and 4 amplifications of the IGF1R-gene on 15q26 (4/16, 25%). All of the tumors with IGF1R amplification were type 3 PPBs. One of the PPBs with gain of chromosome 8 was a type 2 tumor and 6 tumors were type 3 PPBs. All but one PPB showed an IGF1R expression by immunohistochemistry. In our series of 16 PPBs, 25% of the tumors have an amplification of the IGF1R gene and 44% show a gain of chromosome 8. All of the tumors with IGF1R amplification were PPBs type 3, indicating that it is a later event in tumor progression, while the gain of chromosome 8 was found in both type 2 and type 3 tumors indicating that these changes are probably earlier events in tumor development. Furthermore, the strong IGF1R protein expression could be a possible therapeutic target in refractory chemoresistant PPBs.
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Affiliation(s)
- Christian Vokuhl
- 1 Department of Pediatric Pathology, Christian-Albrechts-University Kiel, Kiel, Germany
| | | | - Ivo Leuschner
- 1 Department of Pediatric Pathology, Christian-Albrechts-University Kiel, Kiel, Germany
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Belinsky MG, Cai KQ, Zhou Y, Luo B, Pei J, Rink L, von Mehren M. Succinate dehydrogenase deficiency in a PDGFRA mutated GIST. BMC Cancer 2017; 17:512. [PMID: 28768491 PMCID: PMC5541693 DOI: 10.1186/s12885-017-3499-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Accepted: 07/24/2017] [Indexed: 12/21/2022] Open
Abstract
Background Most gastrointestinal stromal tumors (GISTs) harbor mutually exclusive gain of function mutations in the receptor tyrosine kinase (RTK) KIT (70–80%) or in the related receptor PDGFRA (~10%). These GISTs generally respond well to therapy with the RTK inhibitor imatinib mesylate (IM), although initial response is genotype-dependent. An alternate mechanism leading to GIST oncogenesis is deficiency in the succinate dehydrogenase (SDH) enzyme complex resulting from genetic or epigenetic inactivation of one of the four SDH subunit genes (SDHA, SDHB, SDHC, SDHD, collectively referred to as SDHX). SDH loss of function is generally seen only in GIST lacking RTK mutations, and SDH-deficient GIST respond poorly to imatinib therapy. Methods Tumor and normal DNA from a GIST case carrying the IM-resistant PDGFRA D842V mutation was analyzed by whole exome sequencing (WES) to identify additional potential targets for therapy. The tumors analyzed were separate recurrences following progression on imatinib, sunitinib, and the experimental PDGFRA inhibitor crenolanib. Tumor sections from the GIST case and a panel of ~75 additional GISTs were subjected to immunohistochemistry (IHC) for the SDHB subunit. Results Surprisingly, a somatic, loss of function mutation in exon 4 of the SDHB subunit gene (c.291_292delCT, p.I97Mfs*21) was identified in both tumors. Sanger sequencing confirmed the presence of this inactivating mutation, and IHC for the SDHB subunit demonstrated that these tumors were SDH-deficient. IHC for the SDHB subunit across a panel of ~75 GIST cases failed to detect SDH deficiency in other GISTs with RTK mutations. Conclusions This is the first reported case of a PDGFRA mutant GIST exhibiting SDH-deficiency. A brief discussion of the relevant GIST literature is included. Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3499-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Martin G Belinsky
- Molecular Therapeutics Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA.
| | - Kathy Q Cai
- Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Yan Zhou
- Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Biao Luo
- Molecular Diagnostics Laboratory, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Jianming Pei
- Genomics Services, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Lori Rink
- Molecular Therapeutics Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA
| | - Margaret von Mehren
- Molecular Therapeutics Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA
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40
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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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Sanderson MP, Hofmann MH, Garin-Chesa P, Schweifer N, Wernitznig A, Fischer S, Jeschko A, Meyer R, Moll J, Pecina T, Arnhof H, Weyer-Czernilofsky U, Zahn SK, Adolf GR, Kraut N. The IGF1R/INSR Inhibitor BI 885578 Selectively Inhibits Growth of IGF2-Overexpressing Colorectal Cancer Tumors and Potentiates the Efficacy of Anti-VEGF Therapy. Mol Cancer Ther 2017; 16:2223-2233. [PMID: 28729397 DOI: 10.1158/1535-7163.mct-17-0336] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Revised: 06/16/2017] [Accepted: 06/30/2017] [Indexed: 12/21/2022]
Abstract
Clinical studies of pharmacologic agents targeting the insulin-like growth factor (IGF) pathway in unselected cancer patients have so far demonstrated modest efficacy outcomes, with objective responses being rare. As such, the identification of selection biomarkers for enrichment of potential responders represents a high priority for future trials of these agents. Several reports have described high IGF2 expression in a subset of colorectal cancers, with focal IGF2 amplification being responsible for some of these cases. We defined a novel cut-off value for IGF2 overexpression based on differential expression between colorectal tumors and normal tissue samples. Analysis of two independent colorectal cancer datasets revealed IGF2 to be overexpressed at a frequency of 13% to 22%. An in vitro screen of 34 colorectal cancer cell lines revealed IGF2 expression to significantly correlate with sensitivity to the IGF1R/INSR inhibitor BI 885578. Furthermore, autocrine IGF2 constitutively activated IGF1R and Akt phosphorylation, which was inhibited by BI 885578 treatment. BI 885578 significantly delayed the growth of IGF2-high colorectal cancer xenograft tumors in mice, while combination with a VEGF-A antibody increased efficacy and induced tumor regression. Besides colorectal cancer, IGF2 overexpression was detected in more than 10% of bladder carcinoma, hepatocellular carcinoma and non-small cell lung cancer patient samples. Meanwhile, IGF2-high non-colorectal cancer cells lines displayed constitutive IGF1R phosphorylation and were sensitive to BI 885578. Our findings suggest that IGF2 may represent an attractive patient selection biomarker for IGF pathway inhibitors and that combination with VEGF-targeting agents may further improve clinical outcomes. Mol Cancer Ther; 16(10); 2223-33. ©2017 AACR.
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Affiliation(s)
| | | | | | | | | | | | | | - Reiner Meyer
- Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Jürgen Moll
- Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Thomas Pecina
- Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | | | | | | | | | - Norbert Kraut
- Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
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Schaffrath J, Schmoll HJ, Voigt W, Müller LP, Müller-Tidow C, Mueller T. Efficacy of targeted drugs in germ cell cancer cell lines with differential cisplatin sensitivity. PLoS One 2017; 12:e0178930. [PMID: 28591197 PMCID: PMC5462387 DOI: 10.1371/journal.pone.0178930] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Accepted: 05/22/2017] [Indexed: 12/25/2022] Open
Abstract
Testicular germ cell tumors (TGCTs) are the most common malignancies in men between the age of 15 and 35. Although cisplatin-based chemotherapy is highly effective in advanced disease, approximately 20% of patients have an unfavorable prognosis due to primary or acquired cisplatin resistance. For these patients, new therapeutic options are urgently needed. In numerous tumor entities, combinations of monoclonal antibodies or kinase inhibitors with chemotherapy exerted promising preclinical or clinical results, which have led to new treatment concepts. This prompted us to investigate the activity of different targeted agents alone or in combination with cisplatin in a panel of TGCT cell lines.
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Affiliation(s)
- Judith Schaffrath
- Department of Internal Medicine IV, Oncology/Hematology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Hans-Joachim Schmoll
- Workgroup Clinical Studies in Oncology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Wieland Voigt
- Medical Innovations and Management, Innovation in Oncology, Steinbeis University, Berlin, Germany
| | - Lutz P. Müller
- Department of Internal Medicine IV, Oncology/Hematology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
| | - Carsten Müller-Tidow
- Department of Internal Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany
| | - Thomas Mueller
- Department of Internal Medicine IV, Oncology/Hematology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany
- * E-mail:
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姚 思, 罗 庆. 野生型胃肠间质瘤分子机制研究进展. Shijie Huaren Xiaohua Zazhi 2017; 25:1166-1172. [DOI: 10.11569/wcjd.v25.i13.1166] [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] [Indexed: 02/06/2023] Open
Abstract
胃肠道间质瘤(gastrointestinal stromal tumor, GIST)是消化系最常见的间叶源性肿瘤, 80%-95%GIST存在KIT或PDGFRA基因突变, 未突变者称为野生型GIST(WT-GIST). 目前证实, 突变型GIST对酪氨酸激酶抑制剂(tyrosine kinase inhibitor, TKI)分子靶向治疗有效. 但WT-GIST通常对TKI类药物不敏感, 其分子理论基础、发生机制需明确阐述.
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Huss S, Pasternack H, Ihle MA, Merkelbach-Bruse S, Heitkötter B, Hartmann W, Trautmann M, Gevensleben H, Büttner R, Schildhaus HU, Wardelmann E. Clinicopathological and molecular features of a large cohort of gastrointestinal stromal tumors (GISTs) and review of the literature: BRAF mutations in KIT/PDGFRA wild-type GISTs are rare events. Hum Pathol 2017; 62:206-214. [PMID: 28159677 DOI: 10.1016/j.humpath.2017.01.005] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2016] [Revised: 01/03/2017] [Accepted: 01/05/2017] [Indexed: 12/27/2022]
Abstract
In KIT/PDGFRA wild-type gastrointestinal stromal tumors (wt-GISTs), BRAF mutations are regarded as alternative pathogenic events driving tumorigenesis. In our study, we aimed at analyzing a large cohort (n=444) of GISTs for BRAF mutations using molecular and immunohistochemical methods. More than 3000 GIST samples from caucasian patients were available in our GIST and Sarcoma Registry NRW. Of these, we selected 172 wt-GISTs to evaluate the frequency of BRAF mutations. Furthermore, 272 GISTs with a representative KIT and PDGFRA mutational status were selected. BRAF mutational status was evaluated by high-resolution melting analysis, Sanger sequencing, and VE1 immunohistochemistry. A BRAF mutation (p.V600E) was found in 7 cases (3.9%) of the wt-GIST cohort. In 2 cases, multiple synchronous tumors harbored the same somatic BRAF mutation. VE1 immunohistochemical staining had a sensitivity of 81.8% and a specificity of 97.5% to detect BRAF p.V600E mutations. Analyzing our cases and the cases reported in the literature (n=37), the percentage of intermediate and high-risk BRAF-mutated wt-GISTs (17/31; 54.8%) was comparable to that recorded for large GIST cohorts irrespective of the mutational status. BRAF mutations are rare events in wt-GISTs, and VE1 immunohistochemistry appears to be a valuable pre-screening tool for the detection of BRAF p.V600E mutations. BRAF mutations in GISTs do not seem to have a prognostic value per se. However, as BRAF inhibition represents a therapeutic option to control disease, we suggest the assessment of the BRAF mutational status, especially in the setting of advanced GIST disease.
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Affiliation(s)
- Sebastian Huss
- Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48156 Münster, Germany.
| | - Helen Pasternack
- Pathology of the University Medical Center Schleswig-Holstein, Campus Luebeck and the Research Center Borstel, Leibniz Center for Medicine and Biosciences, Ratzeburger Allee 160, 23538 Luebeck, Germany.
| | - Michaela Angelika Ihle
- Institute of Pathology, University Hospital Cologne, Kerpener Strasse 62, 50937 Cologne, Germany.
| | - Sabine Merkelbach-Bruse
- Institute of Pathology, University Hospital Cologne, Kerpener Strasse 62, 50937 Cologne, Germany.
| | - Birthe Heitkötter
- Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48156 Münster, Germany.
| | - Wolfgang Hartmann
- Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48156 Münster, Germany.
| | - Marcel Trautmann
- Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48156 Münster, Germany.
| | - Heidrun Gevensleben
- Institute of Pathology, University Hospital Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany.
| | - Reinhard Büttner
- Institute of Pathology, University Hospital Cologne, Kerpener Strasse 62, 50937 Cologne, Germany.
| | - Hans-Ulrich Schildhaus
- Institute of Pathology, University Hospital Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, Germany.
| | - Eva Wardelmann
- Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Albert-Schweitzer-Campus 1, 48156 Münster, Germany.
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Integrated genomic analyses identify frequent gene fusion events and VHL inactivation in gastrointestinal stromal tumors. Oncotarget 2016; 7:6538-51. [PMID: 25987131 PMCID: PMC4872731 DOI: 10.18632/oncotarget.3731] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Accepted: 03/10/2015] [Indexed: 01/17/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. We sequenced nine exomes and transcriptomes, and two genomes of GISTs for integrated analyses. We detected 306 somatic variants in nine GISTs and recurrent protein-altering mutations in 29 genes. Transcriptome sequencing revealed 328 gene fusions, and the most frequently involved fusion events were associated with IGF2 fused to several partner genes including CCND1, FUS, and LASP1. We additionally identified three recurrent read-through fusion transcripts: POLA2-CDC42EP2, C8orf42-FBXO25, and STX16-NPEPL1. Notably, we found intragenic deletions in one of three exons of the VHL gene and increased mRNAs of VEGF, PDGF-β, and IGF-1/2 in 56% of GISTs, suggesting a mechanistic link between VHL inactivation and overexpression of hypoxia-inducible factor target genes in the absence of hypoxia. We also identified copy number gain and increased mRNA expression of AMACR, CRIM1, SKP2, and CACNA1E. Mapping of copy number and gene expression results to the KEGG pathways revealed activation of the JAK-STAT pathway in small intestinal GISTs and the MAPK pathway in wild-type GISTs. These observations will allow us to determine the genetic basis of GISTs and will facilitate further investigation to develop new therapeutic options.
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Gu ML, Wang YM, Zhou XX, Yao HP, Zheng S, Xiang Z, Ji F. An inhibitor of the acetyltransferases CBP/p300 exerts antineoplastic effects on gastrointestinal stromal tumor cells. Oncol Rep 2016; 36:2763-2770. [PMID: 27633918 DOI: 10.3892/or.2016.5080] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Accepted: 08/16/2016] [Indexed: 11/06/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasm featured by activated mutations of KIT and PDGFRA. Although overall survival rates have greatly improved by the development of receptor tyrosine kinase inhibitors, most patients ultimately acquire resistance due to secondary mutations of KIT or PDGFRA. Inhibition of the histone acetyltransferases (HATs) CREB‑binding protein (CBP) and p300 results in antineoplastic effects in various cancers. To determine whether CBP/p300 can serve as an antineoplastic target for GISTs, specific short interfering RNA sequences and the selective HAT inhibitor C646 were administered to GIST882 cells. Cell viability, apoptosis and the cell cycle were analysed using the Cell Counting Kit-8, a caspase-3/7 activity assay or Annexin V-fluorescein isothiocyanate/propidium iodide (PI) staining and PI staining. Gene and protein expression levels were measured by quantitative real-time polymerase chain reaction and western blotting, respectively. Transcriptional blockage of CBP, rather than p300, resulted in suppression of cell proliferation. Interestingly, both CBP and p300 depletion enhanced caspase-3/7 activity. A lack of CBP and p300 caused ETS translocation variant 1 (ETV1) downregulation and KIT inhibition in GIST cells. Nevertheless, the absence of CBP, not p300, leads to extracellular signal-regulated kinase 1/2 inactivation and c-Jun NH2-terminal kinase activation, suggesting a more crucial role for CBP than p300 in cell proliferation and survival. Furthermore, proliferation of GIST cells was reduced by administration of C646, a selective HAT inhibitor for CBP/p300. Apoptosis induction and cell cycle arrest were detected after exposure to C646, indicating that its antitumor activities were supported by its antiproliferative and proapoptotic effects. Additionally, C646 treatment attenuated ETV1 protein expression and inactivated KIT-dependent pathways. Taken together, the present study suggests that CBP/p300 may serve as novel antineoplastic targets and that use of the selective HAT inhibitor C646 is a promising antitumor strategy for GISTs.
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Affiliation(s)
- Meng-Li Gu
- Department of Gastroenterology, The First Affiliated Hospital of Medical College of Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Ya-Mei Wang
- Department of Gastroenterology, The First Affiliated Hospital of Medical College of Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Xin-Xin Zhou
- Department of Gastroenterology, The First Affiliated Hospital of Medical College of Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Hang-Ping Yao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Song Zheng
- Department of Oncology, Hangzhou Cancer Hospital, Hangzhou First People's Hospital, Hangzhou, Zhejiang 310006, P.R. China
| | - Zun Xiang
- Department of Gastroenterology, The First Affiliated Hospital of Medical College of Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Feng Ji
- Department of Gastroenterology, The First Affiliated Hospital of Medical College of Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
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Maurel J, López-Pousa A, Calabuig S, Bagué S, Del Muro XG, Sanjuan X, Rubió-Casadevall J, Cuatrecasas M, Martinez-Trufero J, Horndler C, Fra J, Valverde C, Redondo A, Poveda A, Sevilla I, Lainez N, Rubini M, García-Albéniz X, Martín-Broto J, de Alava E. Phosphorylated-insulin growth factor I receptor (p-IGF1R) and metalloproteinase-3 (MMP3) expression in advanced gastrointestinal stromal tumors (GIST). A GEIS 19 study. Clin Sarcoma Res 2016; 6:10. [PMID: 27358721 PMCID: PMC4926286 DOI: 10.1186/s13569-016-0050-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 06/13/2016] [Indexed: 01/04/2023] Open
Abstract
Background Most GISTs have mutations in KIT or PDGFRA. Patients with advanced GIST with KIT exon 9, PDGFRA mutation or WT for KIT and PDGFRA have a worse progression-free survival (PFS) compared to patients with KIT exon 11 mutated tumors. We evaluated the immunohistochemical (IHC) expression of p-IGF1R (Y1316) and MMP3 as predictors of PFS or overall survival (OS). Methods Ninety-two advanced GIST patients included in GEIS-16 study with KIT and PDGFRA mutational information were examined for p-IGF1R (Y1316) and MMP3 expression in a tissue micro-array. To study activation of the IGF1R system, we have used an antibody (anti-pY1316) that specifically recognizes the active phosphorylated form of the IGF1R. DNA was extracted from paraffin-embedded tissues and intronic PCR primers were used to amplify exons 9, 11, 13 and 17 of KIT, 12 and 18 of PDGFRA. Bidirectional sequencing with specific primers was performed on a ABI3100 sequencer using the Big Dye Terminator v3.1 kit. Multivariate model was built using a stepwise automated variable selection approach with criterion to enter the variable in the model of p < 0.10 and criterion to keep the variable in the model of p < 0.05. PFS was computed as the date of imatinib initiation to progression or death. Overall survival was defined as the time from imatinib initiation to death. Results Phospho-IGF1R was expressed only in 9 % (2/22) of cases without KIT mutation. MMP3 expression was detected in 2/5 patients (40 %) with PDGFRA mutation, 1/16 patients (6 %) with WT genotype and 7/71 patients (10 %) of KIT mutant patients. At univariate analysis KIT exon 11/13 mutation had better PFS than patients with exon 9 mutation, PDGFRA mutation or WT genotype (p = 0.021; HR: 0.46; 95 %CI (0.28–0.76). Less than 24 months disease free-interval (HR 24.2, 95 % CI 10.5–55.8), poor performance status (PS) (HR 6.3, 95 % CI 2.5–15.9), extension of disease; >1 organ (HR 1.89; 95 % CI 1.03–3.4) and genotype analysis (HR 0.57, 95 % CI 0.37–0.97) but not immunophenotype analysis (HR 1.53; 95 % CI 0.76–3.06) were the strongest prognostic factors for PFS in the multivariate analysis. Conclusions Our results do not support p-IGF-1R and MMP3 evaluation in non-selected GIST patients but evaluation of this immunophenotype in WT and mutant PDGFR mutation in larger group of GIST patients, deserve merits.
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Affiliation(s)
- Joan Maurel
- Department of Medical Oncology, Hospital Clinic, CIBERehd, Translational Genomics and Targeted Therapeutics in Solid Tumors (IDIBAPS), Barcelona, Spain
| | - Antonio López-Pousa
- Department of Medical Oncology, Hospital Universitario Sant Pau, Barcelona, Spain
| | - Silvia Calabuig
- Molecular Oncology Laboratory, Fundación de Investigación del Hospital General Universitario de Valencia, Valencia, Spain
| | - Silvia Bagué
- Pathology Department, Hospital Universitario Sant Pau, Barcelona, Spain
| | - Xavier Garcia Del Muro
- Department of Medical Oncology, Institut Català d'Oncologia L'Hospitalet, Barcelona, Spain
| | - Xavier Sanjuan
- Pathology Department, Institut Català d'Oncologia L'Hospitalet, Barcelona, Spain
| | | | - Miriam Cuatrecasas
- Pathology Department, Hospital Clínic, CIBERehd, IDIBAPS, Barcelona, Spain
| | | | - Carlos Horndler
- Pathology Department, Hospital Universitario Miguel Servet, Saragossa, Spain
| | - Joaquin Fra
- Department of Medical Oncology, Hospital Central de Asturias, Oviedo, Spain
| | - Claudia Valverde
- Department of Medical Oncology, Hospital Universitario Vall d'Hebron, Barcelona, Spain
| | | | - Andrés Poveda
- Department of Medical Oncology, Fundación Instituto Valenciano de Oncología, Valencia, Spain
| | - Isabel Sevilla
- Department of Medical Oncology, Hospital Universitario Virgen de la Victoria y Regional de Málaga, Málaga, Spain
| | - Nuria Lainez
- Department of Medical Oncology, Hospital de Navarra, Pamplona, Spain
| | - Michele Rubini
- Department of Experimental and Diagnostic Medicine, Department of Epidemiology, University of Ferrara (UNIFE), Emilia-Romagna, Italy
| | | | - Javier Martín-Broto
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
| | - Enrique de Alava
- Pathology Department, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain
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Novel receptor tyrosine kinase targeted combination therapies for imatinib-resistant gastrointestinal stromal tumors (GIST). Oncotarget 2015; 6:1954-66. [PMID: 25557174 PMCID: PMC4385828 DOI: 10.18632/oncotarget.3021] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Accepted: 12/09/2015] [Indexed: 12/31/2022] Open
Abstract
Background: c-Kit/α-PDGFR targeted therapies are effective for gastrointestinal stromal tumors (GIST), but, >50% develop drug resistance. Methods: RTK expression (c-Kit, c-Met, AXL, HER-1, HER-2, IGF-1R) in pre-/post-imatinib (IM) GIST patient samples (n=16) and 4 GIST cell lines were examined for RTK inhibitor activity. GIST-882 cells were cultured in IM every other day, cells collected (1 week to 6 months) and analyzed by qRT-PCR and Western blotting. Results: Immunohistochemistry pre-/post-IM demonstrated continued expression of c-Kit and HER1, while a subset expressed IGF-1R, c-Met and AXL. In GIST cells (GIST-882, GIST430/654, GIST48) c-Kit, HER1 and c-Met are co-expressed. Acute IM over-express c-Kit while chronic IM, lose c-Kit and HER-1 in GIST882 cells. GIST882 and GIST430/654 cells have an IC50 0.077 and 0.59 μM to IM respectively. GIST48 have an IC50 0.66 μM to IM, 0.91 μM to amuvatinib [AMU] and 0.67 μM to erlotinib (Erl). Synergistic combinations: GIST882, AMU + Erl (CI 0.20); IM + AMU (CI 0.50), GIST430/654, IM + afatinib (CI 0.39); IM + AMU (CI 0.42), GIST48, IM + afatinib (CI 0.03); IM + AMU (CI 0.04); AMU + afatinib (CI 0.36); IM + Erl (CI 0.63). Conclusion: Targeting c-Kit plus HER1 or AXL/c-Met abrogates IM resistance in GIST.
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Back J, Jeanty J, Landas S. Gastrointestinal stromal tumor of the appendix: case report and review of the literature. HUMAN PATHOLOGY: CASE REPORTS 2015. [DOI: 10.1016/j.ehpc.2015.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
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50
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Belinsky MG, Rink L, Cai KQ, Capuzzi SJ, Hoang Y, Chien J, Godwin AK, von Mehren M. Somatic loss of function mutations in neurofibromin 1 and MYC associated factor X genes identified by exome-wide sequencing in a wild-type GIST case. BMC Cancer 2015; 15:887. [PMID: 26555092 PMCID: PMC4641358 DOI: 10.1186/s12885-015-1872-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Accepted: 10/30/2015] [Indexed: 12/25/2022] Open
Abstract
Background Approximately 10–15 % of gastrointestinal stromal tumors (GISTs) lack gain of function mutations in the KIT and platelet-derived growth factor receptor alpha (PDGFRA) genes. An alternate mechanism of oncogenesis through loss of function of the succinate-dehydrogenase (SDH) enzyme complex has been identified for a subset of these “wild type” GISTs. Methods Paired tumor and normal DNA from an SDH-intact wild-type GIST case was subjected to whole exome sequencing to identify the pathogenic mechanism(s) in this tumor. Selected findings were further investigated in panels of GIST tumors through Sanger DNA sequencing, quantitative real-time PCR, and immunohistochemical approaches. Results A hemizygous frameshift mutation (p.His2261Leufs*4), in the neurofibromin 1 (NF1) gene was identified in the patient’s GIST; however, no germline NF1 mutation was found. A somatic frameshift mutation (p.Lys54Argfs*31) in the MYC associated factor X (MAX) gene was also identified. Immunohistochemical analysis for MAX on a large panel of GISTs identified loss of MAX expression in the MAX-mutated GIST and in a subset of mainly KIT-mutated tumors. Conclusion This study suggests that inactivating NF1 mutations outside the context of neurofibromatosis may be the oncogenic mechanism for a subset of sporadic GIST. In addition, loss of function mutation of the MAX gene was identified for the first time in GIST, and a broader role for MAX in GIST progression was suggested. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1872-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Martin G Belinsky
- Molecular Therapeutics Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA.
| | - Lori Rink
- Molecular Therapeutics Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA.
| | - Kathy Q Cai
- Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA.
| | - Stephen J Capuzzi
- Molecular Therapeutics Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA. .,Division of Chemical Biology and Medicinal Chemistry, University of North Carolina, Chapel Hill, NC, USA.
| | - Yen Hoang
- Department of Bioinformatics and Biosystems Technology, University of Applied Sciences Wildau, Wildau, Germany. .,Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA.
| | - Jeremy Chien
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA.
| | - Andrew K Godwin
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
| | - Margaret von Mehren
- Molecular Therapeutics Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA.
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