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Zhao Z, Qiu S, Zhang X, Liu S, Wang L, Guan H, He J, Hu Y, Li X, Luo S, Chen Z, Mo T, Zhang Y, Zhao X, Pan Y, Ding H, Cao J, Pan J. Characterization of a novel cell line established from mice gastrointestinal stromal model by chemical induction. Transl Oncol 2025; 56:102388. [PMID: 40233502 DOI: 10.1016/j.tranon.2025.102388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 02/03/2025] [Accepted: 04/05/2025] [Indexed: 04/17/2025] Open
Abstract
BACKGROUND Gastrointestinal stromal tumors (GISTs) are a type of tumor that originates from gastrointestinal mesenchymal tissue. Although several somatic or germline mutation GIST mice were established, however, there is still a lack of an authentic mice GIST cell lines for further experimental study. METHODS We developed a chemically induced C57BL/6 J GIST model using 3- methylcholanthrene. Tumor characteristics were confirmed through histology and IHC. Primary cells were isolated to establish the mGSTc01 cell line, and molecular profiling was conducted. Additionally, we established GIST model in immunocompetent mice to evaluate their sensitivity to imatinib. RESULTS Our study successfully developed a chemically induced murine GIST model, characterized by positive staining of c-kit and DOG-1. The mGSTc01 monoclonal cell line exhibited slender morphology and expressed the c-kit marker, Whole exome sequencing uncovered mutations of Lamb1, MMP9, and c-kit in GIST cells and provided a detailed picture of the entire genome's copy number variations. RNA sequencing indicated genes associated with cell adhesion and focal adhesion were enriched in mGSTc01 cells. The mGSTc01 cells demonstrated obvious malignant behaviors, notably elevated migration, adhesion, and proliferation. In immunocompetent mice, subcutaneous xenografts not only reserved the aggressive phenotype but also displayed a response to imatinib, underscoring the model's applicability for advancing therapeutic research. CONCLUSION We firstly established a mGSTc01 cell line derived from C57BL/6 J mice GIST tumor offers, which closely mimicking human disease characteristics. It is a potent platform for investigating tumor microenvironment of GIST in mice model, and provides a novel way for new therapeutic discoveries in GIST.
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Affiliation(s)
- Zhan Zhao
- Department of General Surgery, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, PR China
| | - Shenghui Qiu
- Department of General Surgery, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, PR China; Department of General Surgery, Guangzhou First People's Hospital, Guangzhou, 510180, PR China
| | - Xiangwei Zhang
- Department of General Surgery, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, PR China
| | - Shijin Liu
- Department of General Surgery, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, PR China
| | - Lu Wang
- Institute of Precision Cancer Medicine and Pathology, Jinan University Medical College, Guangzhou, Guangdong, 510632, PR China
| | - Hanyang Guan
- Department of General Surgery, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, PR China
| | - Jiashuai He
- Department of General Surgery, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, PR China
| | - Yangzhi Hu
- The Affiliated Hospital of Xiangnan University, Chenzhou, Hunan, PR China
| | - Xiaobo Li
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, 510632, China
| | - Simin Luo
- Department of Bone and Joint Surgery, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong Province, China
| | - Zuyang Chen
- Department of General Surgery, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, PR China
| | - Tianmu Mo
- Department of General Surgery, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, PR China
| | - Yiran Zhang
- Department of General Surgery, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, PR China
| | - Xiaoxu Zhao
- Department of General Surgery, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, PR China
| | - Yunlong Pan
- Department of General Surgery, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, PR China
| | - Hui Ding
- Department of General Surgery, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, PR China.
| | - Jie Cao
- Department of General Surgery, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, PR China; Department of General Surgery, Guangzhou First People's Hospital, Guangzhou, 510180, PR China.
| | - Jinghua Pan
- Department of General Surgery, The First Affiliated Hospital of Jinan University, 510632, Guangzhou, Guangdong, PR China.
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Zhang W, Wang S, Zhang H, Meng Y, Jiao S, An L, Zhou Z. Modeling human gastric cancers in immunocompetent mice. Cancer Biol Med 2024; 21:j.issn.2095-3941.2024.0124. [PMID: 38940675 PMCID: PMC11271222 DOI: 10.20892/j.issn.2095-3941.2024.0124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 05/14/2024] [Indexed: 06/29/2024] Open
Abstract
Gastric cancer (GC) is a major cause of cancer-related mortality worldwide. GC is determined by multiple (epi)genetic and environmental factors; can occur at distinct anatomic positions of the stomach; and displays high heterogeneity, with different cellular origins and diverse histological and molecular features. This heterogeneity has hindered efforts to fully understand the pathology of GC and develop efficient therapeutics. In the past decade, great progress has been made in the study of GC, particularly in molecular subtyping, investigation of the immune microenvironment, and defining the evolutionary path and dynamics. Preclinical mouse models, particularly immunocompetent models that mimic the cellular and molecular features of human GC, in combination with organoid culture and clinical studies, have provided powerful tools for elucidating the molecular and cellular mechanisms underlying GC pathology and immune evasion, and the development of novel therapeutic strategies. Herein, we first briefly introduce current progress and challenges in GC study and subsequently summarize immunocompetent GC mouse models, emphasizing the potential application of genetically engineered mouse models in antitumor immunity and immunotherapy studies.
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Affiliation(s)
- Weihong Zhang
- Department of Stomatology, Department of Medical Ultrasound, Shanghai Tenth People’s Hospital, Tongji University Cancer Center, Tongji University School of Medicine, Shanghai 200072, China
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Shilong Wang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Hui Zhang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Yan Meng
- Department of Stomatology, Department of Medical Ultrasound, Shanghai Tenth People’s Hospital, Tongji University Cancer Center, Tongji University School of Medicine, Shanghai 200072, China
| | - Shi Jiao
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Liwei An
- Department of Stomatology, Department of Medical Ultrasound, Shanghai Tenth People’s Hospital, Tongji University Cancer Center, Tongji University School of Medicine, Shanghai 200072, China
| | - Zhaocai Zhou
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200032, China
- Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing 211166, China
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3
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Etherington MS, Hanna AN, Medina BD, Liu M, Tieniber AD, Kwak HV, Tardy KJ, Levin L, Do KJ, Rossi F, Zeng S, DeMatteo RP. Tyrosine Kinase Inhibition Activates Intratumoral γδ T Cells in Gastrointestinal Stromal Tumor. Cancer Immunol Res 2024; 12:107-119. [PMID: 37922405 PMCID: PMC10842124 DOI: 10.1158/2326-6066.cir-23-0061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 05/09/2023] [Accepted: 10/31/2023] [Indexed: 11/05/2023]
Abstract
γδ T cells are a rare but potent subset of T cells with pleiotropic functions. They commonly reside within tumors but the response of γδ T cells to tyrosine kinase inhibition is unknown. To address this, we studied a genetically engineered mouse model of gastrointestinal stromal tumor (GIST) driven by oncogenic Kit signaling that responds to the Kit inhibitor imatinib. At baseline, γδ T cells were antitumoral, as blockade of either γδ T-cell receptor or IL17A increased tumor weight and decreased antitumor immunity. However, imatinib therapy further stimulated intratumoral γδ T cells, as determined by flow cytometry and single-cell RNA sequencing (scRNA-seq). Imatinib expanded a highly activated γδ T-cell subset with increased IL17A production and higher expression of immune checkpoints and cytolytic effector molecules. Consistent with the mouse model, γδ T cells produced IL17A in fresh human GIST specimens, and imatinib treatment increased γδ T-cell gene signatures, as measured by bulk tumor RNA-seq. Furthermore, tumor γδ T cells correlated with survival in patients with GIST. Our findings highlight the interplay between tumor cell oncogene signaling and antitumor immune responses and identify γδ T cells as targets for immunotherapy in GIST.
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Affiliation(s)
- Mark S Etherington
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Andrew N Hanna
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Benjamin D Medina
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Mengyuan Liu
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Andrew D Tieniber
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Hyunjee V Kwak
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Katherine J Tardy
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Lillian Levin
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Kevin J Do
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Ferdinando Rossi
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Shan Zeng
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Ronald P DeMatteo
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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Jumaniyazova E, Lokhonina A, Dzhalilova D, Kosyreva A, Fatkhudinov T. Immune Cells in the Tumor Microenvironment of Soft Tissue Sarcomas. Cancers (Basel) 2023; 15:5760. [PMID: 38136307 PMCID: PMC10741982 DOI: 10.3390/cancers15245760] [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: 11/14/2023] [Revised: 12/04/2023] [Accepted: 12/06/2023] [Indexed: 12/24/2023] Open
Abstract
Soft tissue sarcomas (STSs) are a rare heterogeneous group of malignant neoplasms characterized by their aggressive course and poor response to treatment. This determines the relevance of research aimed at studying the pathogenesis of STSs. By now, it is known that STSs is characterized by complex relationships between the tumor cells and immune cells of the microenvironment. Dynamic interactions between tumor cells and components of the microenvironment enhance adaptation to changing environmental conditions, which provides the high aggressive potential of STSs and resistance to antitumor therapy. Today, active research is being conducted to find effective antitumor drugs and to evaluate the possibility of using therapy with immune cells of STS. The difficulty in assessing the efficacy of new antitumor options is primarily due to the high heterogeneity of this group of malignant neoplasms. Studying the role of immune cells in the microenvironment in the progression STSs and resistance to antitumor therapies will provide the discovery of new biomarkers of the disease and the prediction of response to immunotherapy. In addition, it will help to initially divide patients into subgroups of good and poor response to immunotherapy, thus avoiding wasting precious time in selecting the appropriate antitumor agent.
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Affiliation(s)
- Enar Jumaniyazova
- Research Institute of Molecular and Cellular Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia (T.F.)
| | - Anastasiya Lokhonina
- Research Institute of Molecular and Cellular Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia (T.F.)
- Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418 Moscow, Russia
- National Medical Research Center for Obstetrics, Gynecology and Perinatology Named after Academician V.I. Kulakov of Ministry of Healthcare of Russian Federation, 4 Oparina Street, 117997 Moscow, Russia
| | - Dzhuliia Dzhalilova
- Research Institute of Molecular and Cellular Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia (T.F.)
- Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418 Moscow, Russia
| | - Anna Kosyreva
- Research Institute of Molecular and Cellular Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia (T.F.)
- Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418 Moscow, Russia
| | - Timur Fatkhudinov
- Research Institute of Molecular and Cellular Medicine, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, 117198 Moscow, Russia (T.F.)
- Avtsyn Research Institute of Human Morphology of Petrovsky National Research Centre of Surgery, 3 Tsyurupy Street, 117418 Moscow, Russia
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5
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Costa A, Gozzellino L, Nannini M, Astolfi A, Pantaleo MA, Pasquinelli G. Preclinical Models of Visceral Sarcomas. Biomolecules 2023; 13:1624. [PMID: 38002306 PMCID: PMC10669128 DOI: 10.3390/biom13111624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 10/30/2023] [Accepted: 11/02/2023] [Indexed: 11/26/2023] Open
Abstract
Visceral sarcomas are a rare malignant subgroup of soft tissue sarcomas (STSs). STSs, accounting for 1% of all adult tumors, are derived from mesenchymal tissues and exhibit a wide heterogeneity. Their rarity and the high number of histotypes hinder the understanding of tumor development mechanisms and negatively influence clinical outcomes and treatment approaches. Although some STSs (~20%) have identifiable genetic markers, as specific mutations or translocations, most are characterized by complex genomic profiles. Thus, identification of new therapeutic targets and development of personalized therapies are urgent clinical needs. Although cell lines are useful for preclinical investigations, more reliable preclinical models are required to develop and test new potential therapies. Here, we provide an overview of the available in vitro and in vivo models of visceral sarcomas, whose gene signatures are still not well characterized, to highlight current challenges and provide insights for future studies.
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Affiliation(s)
- Alice Costa
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
| | - Livia Gozzellino
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
| | - Margherita Nannini
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Annalisa Astolfi
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
| | - Maria Abbondanza Pantaleo
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Gianandrea Pasquinelli
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
- Division of Pathology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
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6
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Hu X, Su P, Liu B, Guo J, Wang Z, He C, Wang Z, Kou Y. Characterization of a Human Gastrointestinal Stromal Tumor Cell Line Established by SV40LT-Mediated Immortalization. Int J Mol Sci 2023; 24:13640. [PMID: 37686448 PMCID: PMC10487453 DOI: 10.3390/ijms241713640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Revised: 08/20/2023] [Accepted: 08/25/2023] [Indexed: 09/10/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the digestive tract and originate from the interstitial cells of Cajal (ICC), which is the pacemaker for peristaltic movement in the gastrointestinal tract. Existing GIST cell lines are widely used as cell models for in vitro experimental studies because the mutation sites are known. However, the immortalization methods of these cell lines are unknown, and no Chinese patient-derived GIST cell lines have been documented. Here, we transfected simian virus 40 large T antigen (SV40LT) into primary GIST cells to establish an immortalized human GIST cell line (ImGIST) for the first time. The ImGIST cells had neuronal cell-like irregular radioactive growth and retained the fusion growth characteristics of GIST cells. They stably expressed signature proteins, maintained the biological and genomic characteristics of normal primary GIST cells, and responded well to imatinib, suggesting that ImGIST could be a potential in vitro model for research in GIST to explore the molecular pathogenesis, drug resistance mechanisms, and the development of new adjuvant therapeutic options.
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Affiliation(s)
- Xiangchen Hu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China; (X.H.)
| | - Peng Su
- Medical Research Center, Shengjing Hospital of China Medical University, Shenyang 117005, China
| | - Bo Liu
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China; (X.H.)
| | - Jingwei Guo
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Zitong Wang
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Cai He
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Zhe Wang
- Department of Pathology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Youwei Kou
- Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang 110004, China; (X.H.)
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Tieniber AD, Rossi F, Hanna AN, Liu M, Etherington MS, Loo JK, Param N, Zeng S, Do K, Wang L, DeMatteo RP. Multiple intratumoral sources of kit ligand promote gastrointestinal stromal tumor. Oncogene 2023; 42:2578-2588. [PMID: 37468679 DOI: 10.1038/s41388-023-02777-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 06/22/2023] [Accepted: 07/05/2023] [Indexed: 07/21/2023]
Abstract
Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and is typically driven by a single mutation in the Kit or PDGFRA receptor. While highly effective, tyrosine kinase inhibitors (TKIs) are not curative. The natural ligand for the Kit receptor is Kit ligand (KitL), which exists in both soluble and membrane-bound forms. While KitL is known to stimulate human GIST cell lines in vitro, we used a genetically engineered mouse model of GIST containing a common human KIT mutation to investigate the intratumoral sources of KitL, importance of KitL during GIST oncogenesis, and contribution of soluble KitL to tumor growth in vivo. We discovered that in addition to tumor cells, endothelia and smooth muscle cells produced KitL in KitV558Δ/+ tumors, even after imatinib therapy. Genetic reduction of total KitL in tumor cells of KitV558Δ/+ mice impaired tumor growth in vivo. Similarly, genetic reduction of tumor cell soluble KitL in KitV558Δ/+ mice decreased tumor size. By RNA sequencing, quantitative PCR, and immunohistochemistry, KitL expression was heterogeneous in human GIST specimens. In particular, PDGFRA-mutant tumors had much higher KitL expression than Kit-mutant tumors, suggesting the benefit of Kit activation in the absence of mutant KIT. Serum KitL was higher in GIST patients with tumors resistant to imatinib and in those with tumors expressing more KitL RNA. Overall, KitL supports the growth of GIST at baseline and after imatinib therapy and remains a potential biomarker and therapeutic target.
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Affiliation(s)
- Andrew D Tieniber
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Ferdinando Rossi
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Andrew N Hanna
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Marion Liu
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Mark S Etherington
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Jennifer K Loo
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Nesteene Param
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Shan Zeng
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Kevin Do
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Laura Wang
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
| | - Ronald P DeMatteo
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
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Li B, Chen H, Yang S, Chen F, Xu L, Li Y, Li M, Zhu C, Shao F, Zhang X, Deng C, Zeng L, He Y, Zhang C. Advances in immunology and immunotherapy for mesenchymal gastrointestinal cancers. Mol Cancer 2023; 22:71. [PMID: 37072770 PMCID: PMC10111719 DOI: 10.1186/s12943-023-01770-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 03/29/2023] [Indexed: 04/20/2023] Open
Abstract
Mesenchymal gastrointestinal cancers are represented by the gastrointestinal stromal tumors (GISTs) which occur throughout the whole gastrointestinal tract, and affect human health and economy globally. Curative surgical resections and tyrosine kinase inhibitors (TKIs) are the main managements for localized GISTs and recurrent/metastatic GISTs, respectively. Despite multi-lines of TKIs treatments prolonged the survival time of recurrent/metastatic GISTs by delaying the relapse and metastasis of the tumor, drug resistance developed quickly and inevitably, and became the huge obstacle for stopping disease progression. Immunotherapy, which is typically represented by immune checkpoint inhibitors (ICIs), has achieved great success in several solid tumors by reactivating the host immune system, and been proposed as an alternative choice for GIST treatment. Substantial efforts have been devoted to the research of immunology and immunotherapy for GIST, and great achievements have been made. Generally, the intratumoral immune cell level and the immune-related gene expressions are influenced by metastasis status, anatomical locations, driver gene mutations of the tumor, and modulated by imatinib therapy. Systemic inflammatory biomarkers are regarded as prognostic indicators of GIST and closely associated with its clinicopathological features. The efficacy of immunotherapy strategies for GIST has been widely explored in pre-clinical cell and mouse models and clinical experiments in human, and some patients did benefit from ICIs. This review comprehensively summarizes the up-to-date advancements of immunology, immunotherapy and research models for GIST, and provides new insights and perspectives for future studies.
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Affiliation(s)
- Bo Li
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China
| | - Hui Chen
- Shenzhen Key Laboratory of Chinese Medicine Active Substance Screening and Translational Research, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China
| | - Shaohua Yang
- Guangdong-Hong Kong-Macau University Joint Laboratory of Digestive Cancer Research, Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China
| | - Feng Chen
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China
| | - Liangliang Xu
- Shenzhen Key Laboratory for Drug Addiction and Medication Safety, Department of Ultrasound, Peking University Shenzhen Hospital, Shenzhen, 518036, China
| | - Yan Li
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China
| | - Mingzhe Li
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China
| | - Chengming Zhu
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China
| | - Fangyuan Shao
- MOE Frontiers Science Center for Precision Oncology, Faculty of Health Sciences, Institute of Translational Medicine, Cancer Center, University of Macau, Macau SAR, 999078, China
| | - Xinhua Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-Sen University, No. 58 Zhongshan Road, Guangzhou, 510080, China
| | - Chuxia Deng
- MOE Frontiers Science Center for Precision Oncology, Faculty of Health Sciences, Institute of Translational Medicine, Cancer Center, University of Macau, Macau SAR, 999078, China.
| | - Leli Zeng
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China.
| | - Yulong He
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China.
| | - Changhua Zhang
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China.
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Klein-Rodewald T, Micklich K, Sanz-Moreno A, Tost M, Calzada-Wack J, Adler T, Klaften M, Sabrautzki S, Aigner B, Kraiger M, Gailus-Durner V, Fuchs H, Gründer A, Pahl H, Wolf E, Hrabe de Angelis M, Rathkolb B, Rozman J, Puk O, Schrewe A, Schulz H, Adamski J, Busch DH, Esposito I, Wurst W, Stoeger C, Gründer A, Pahl H, Wolf E, Hrabe de Angelis M, Rathkolb B. New C3H Kit N824K/WT cancer mouse model develops late-onset malignant mammary tumors with high penetrance. Sci Rep 2022; 12:19793. [PMID: 36396684 PMCID: PMC9671887 DOI: 10.1038/s41598-022-23218-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 10/26/2022] [Indexed: 11/18/2022] Open
Abstract
Gastro-intestinal stromal tumors and acute myeloid leukemia induced by activating stem cell factor receptor tyrosine kinase (KIT) mutations are highly malignant. Less clear is the role of KIT mutations in the context of breast cancer. Treatment success of KIT-induced cancers is still unsatisfactory because of primary or secondary resistance to therapy. Mouse models offer essential platforms for studies on molecular disease mechanisms in basic cancer research. In the course of the Munich N-ethyl-N-nitrosourea (ENU) mutagenesis program a mouse line with inherited polycythemia was established. It carries a base-pair exchange in the Kit gene leading to an amino acid exchange at position 824 in the activation loop of KIT. This KIT variant corresponds to the N822K mutation found in human cancers, which is associated with imatinib-resistance. C3H KitN824K/WT mice develop hyperplasia of interstitial cells of Cajal and retention of ingesta in the cecum. In contrast to previous Kit-mutant models, we observe a benign course of gastrointestinal pathology associated with prolonged survival. Female mutants develop mammary carcinomas at late onset and subsequent lung metastasis. The disease model complements existing oncology research platforms. It allows for addressing the role of KIT mutations in breast cancer and identifying genetic and environmental modifiers of disease progression.
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Affiliation(s)
- Tanja Klein-Rodewald
- grid.4567.00000 0004 0483 2525Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Kateryna Micklich
- grid.4567.00000 0004 0483 2525Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Adrián Sanz-Moreno
- grid.4567.00000 0004 0483 2525Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Monica Tost
- grid.4567.00000 0004 0483 2525Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Julia Calzada-Wack
- grid.4567.00000 0004 0483 2525Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Thure Adler
- grid.4567.00000 0004 0483 2525Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Matthias Klaften
- grid.4567.00000 0004 0483 2525Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany ,Present Address: amcure GmbH, Herrman-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
| | - Sibylle Sabrautzki
- grid.4567.00000 0004 0483 2525Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany ,grid.4567.00000 0004 0483 2525Research Unit Comparative Medicine, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Bernhard Aigner
- grid.5252.00000 0004 1936 973XInstitute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Markus Kraiger
- grid.4567.00000 0004 0483 2525Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Valerie Gailus-Durner
- grid.4567.00000 0004 0483 2525Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Helmut Fuchs
- grid.4567.00000 0004 0483 2525Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | | | - Albert Gründer
- grid.7708.80000 0000 9428 7911Section of Molecular Hematology, Department of Hematology/Oncology, Universitäts Klinikum Freiburg, Freiburg, Germany
| | - Heike Pahl
- grid.7708.80000 0000 9428 7911Section of Molecular Hematology, Department of Hematology/Oncology, Universitäts Klinikum Freiburg, Freiburg, Germany
| | - Eckhard Wolf
- grid.5252.00000 0004 1936 973XInstitute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Martin Hrabe de Angelis
- grid.4567.00000 0004 0483 2525Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany ,grid.452622.5German Center for Diabetes Research (DZD), Neuherberg, Germany ,grid.6936.a0000000123222966Chair of Experimental Genetics, TUM School of Life Sciences, Technische Universität München, Freising, Germany
| | - Birgit Rathkolb
- grid.4567.00000 0004 0483 2525Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany ,grid.5252.00000 0004 1936 973XInstitute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany ,grid.452622.5German Center for Diabetes Research (DZD), Neuherberg, Germany
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10
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Kraiger M, Klein-Rodewald T, Rathkolb B, Calzada-Wack J, Sanz-Moreno A, Fuchs H, Wolf E, Gailus-Durner V, de Angelis MH. Monitoring longitudinal disease progression in a novel murine Kit tumor model using high-field MRI. Sci Rep 2022; 12:14608. [PMID: 36028522 PMCID: PMC9418174 DOI: 10.1038/s41598-022-17880-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 08/02/2022] [Indexed: 11/09/2022] Open
Abstract
Animal models are an indispensable platform used in various research disciplines, enabling, for example, studies of basic biological mechanisms, pathological processes and new therapeutic interventions. In this study, we applied magnetic resonance imaging (MRI) to characterize the clinical picture of a novel N-ethyl-N-nitrosourea-induced Kit-mutant mouse in vivo. Seven C3H KitN824K/WT mutant animals each of both sexes and their littermates were monitored every other month for a period of twelve months. MRI relaxometry data of hematopoietic bone marrow and splenic tissue as well as high-resolution images of the gastrointestinal organs were acquired. Compared with controls, the mutants showed a dynamic change in the shape and volume of the cecum and enlarged Peyer´s patches were identified throughout the entire study. Mammary tumors were observed in the majority of mutant females and were first detected at eight months of age. Using relaxation measurements, a substantial decrease in longitudinal relaxation times in hematopoietic tissue was detected in mutants at one year of age. In contrast, transverse relaxation time of splenic tissue showed no differences between genotypes, except in two mutant mice, one of which had leukemia and the other hemangioma. In this study, in vivo MRI was used for the first time to thoroughly characterize the evolution of systemic manifestations of a novel Kit-induced tumor model and to document the observable organ-specific disease cascade.
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Affiliation(s)
- Markus Kraiger
- Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
| | - Tanja Klein-Rodewald
- Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Birgit Rathkolb
- Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- German Center for Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Julia Calzada-Wack
- Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Adrián Sanz-Moreno
- Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Helmut Fuchs
- Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Eckhard Wolf
- Institute of Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Valérie Gailus-Durner
- Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Martin Hrabě de Angelis
- Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- German Center for Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- Chair of Experimental Genetics, TUM School of Life Sciences, Technische Universität München, Freising, Germany
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11
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Ueda K, Takanosu M, Kagawa Y, Ueda A, Ano N, Nomura K, Ozaki K. Gastrointestinal stromal tumors with Kit gene mutation in 4 guinea pigs ( Cavia porcellus). Vet Pathol 2022; 59:740-746. [PMID: 35393902 DOI: 10.1177/03009858221087630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Gastrointestinal stromal tumors (GISTs) have been rarely reported in guinea pigs. We aimed to characterize the clinical and pathological features of GISTs in 4 guinea pigs and investigate the presence of mutations in exon 11 of the KIT proto-oncogene receptor tyrosine kinase (Kit) gene. Two subjects were male and 2 were female; 2 were 6 years old, 1 was 7 years old, and 1 was of an unknown age. Three cases had primary gastric tumors, whereas 1 had a primary small intestinal tumor. All cases had tumors that extended from the submucosa to the serosa with extraluminal growth. A gastric tumor had gastric, pancreatic, and cecal metastases. Histologically, the tumors were sharply demarcated and composed of spindle cells arranged in bundles, intermixed with small amounts of collagenous stroma. The tumor cells had mild atypia with few mitotic figures (0-5/50 high power fields, 7.95 mm2) and were immunolabeled for KIT and Discovered-on-GIST 1 (DOG1). All cases had mutations in exon 11 of the Kit gene. These findings indicate that GISTs in guinea pigs are similar to those in humans and dogs. GISTs in guinea pigs are potentially malignant submucosal tumors with KIT- and DOG1-immunolabeling, exon 11 KIT mutations, and the possibility of metastasis.
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Affiliation(s)
- Kengo Ueda
- Vogel Animal Hospital, Kobe, Hyogo, Japan.,Setsunan University, Hirakata, Osaka, Japan
| | | | | | - Akiko Ueda
- Vogel Animal Hospital, Kobe, Hyogo, Japan
| | - Naoko Ano
- Marupi Lifetech Co., Ltd., Ikeda, Osaka, Japan
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12
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Dermawan JK, Rubin BP. Molecular Pathogenesis of Gastrointestinal Stromal Tumor: A Paradigm for Personalized Medicine. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2021; 17:323-344. [PMID: 34736340 DOI: 10.1146/annurev-pathol-042220-021510] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Over the past three to four decades, the molecular pathogenesis of gastrointestinal stromal tumors (GISTs) has been elucidated in great detail. In this review, we discuss the biological genesis of GISTs, identification of the various primary activating driver mutations (focusing on KIT and PDGFRA), oncogene addiction and targeted therapies with imatinib and other tyrosine kinase inhibitors, and the subsequent characterization of the various mechanisms of drug resistance. We illustrate how GIST has become a quintessential paradigm for personalized medicine. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Josephine K Dermawan
- Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA; ,
| | - Brian P Rubin
- Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA; ,
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13
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Kihara T, Yuan J, Watabe T, Kitajima K, Kimura N, Ohkouchi M, Hashikura Y, Ohkubo S, Takahashi T, Hirota S. Pimitespib is effective on cecal GIST in a mouse model of familial GISTs with KIT-Asp820Tyr mutation through KIT signaling inhibition. Exp Mol Pathol 2021; 123:104692. [PMID: 34606780 DOI: 10.1016/j.yexmp.2021.104692] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 08/10/2021] [Accepted: 09/28/2021] [Indexed: 01/01/2023]
Abstract
Three families with multiple gastrointestinal stromal tumors (GISTs) caused by a germline Asp820Tyr mutation at exon 17 of the c-kit gene (KIT-Asp820Tyr) have been reported. We previously generated a knock-in mouse model of the family, and the mice with KIT-Asp818Tyr corresponding to human KIT-Asp820Tyr showed a cecal tumor equivalent to human GIST. In the model mice, we reported that tyrosine kinase inhibitor, imatinib, could stabilize but not decrease the cecal tumor volume. In this report, we examined whether a heat shock protein 90 inhibitor, pimitespib (TAS-116), has an inhibitory effect on phosphorylation of KIT-Asp818Tyr and can decrease the cecal tumor volume in the model mice. First, we showed that pimitespib inhibited KIT phosphorylation both dose- and time-dependently in KIT-Asp818Tyr transfected murine Ba/F3 cells. Then, four 1-week courses of pimitespib were orally administered to heterozygous (KIT-Asp818Tyr/+) model mice. Each course consisted of once-daily administration for consecutive 5 days followed by 2 days-off. Cecal tumors were dissected, and tumor volume was histologically analyzed, Ki-67 labeling index was immunohistochemically examined, and apoptotic figures were counted. Compared to the vehicle treated mice, pimitespib administered mice showed statistically significantly smaller cecal tumor volume, lower Ki-67 labeling index, and higher number of apoptotic figures in 10 high power fields (P = 0.0344, P = 0.0019 and P = 0.0269, respectively). Western blotting revealed that activation of KIT signaling molecules was strongly inhibited in the tumor tissues of pimitespib-administered mice compared to control mice. Thus, pimitespib seemed to inhibit in vivo tumor progression effectively in the model mice. These results suggest that the progression of multiple GISTs in patients with germline KIT-Asp820Tyr might be controllable by pimitespib.
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Affiliation(s)
- Takako Kihara
- Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Jiayin Yuan
- Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Tadashi Watabe
- Department of Radiology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Kazuhiro Kitajima
- Department of Radiology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Neinei Kimura
- Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Mizuka Ohkouchi
- Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Yuka Hashikura
- Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Japan
| | - Shuichi Ohkubo
- Discovery and Preclinical Research Division, Taiho Pharmaceutical Co. Ltd, Tsukuba, Japan
| | - Tsuyoshi Takahashi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan
| | - Seiichi Hirota
- Department of Surgical Pathology, Hyogo College of Medicine, Nishinomiya, Japan.
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14
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Yebra M, Bhargava S, Kumar A, Burgoyne AM, Tang CM, Yoon H, Banerjee S, Aguilera J, Cordes T, Sheth V, Noh S, Ustoy R, Li S, Advani SJ, Corless CL, Heinrich MC, Kurzrock R, Lippman SM, Fanta PT, Harismendy O, Metallo C, Sicklick JK. Establishment of Patient-Derived Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumor Models for Predicting Therapeutic Response. Clin Cancer Res 2021; 28:187-200. [PMID: 34426440 DOI: 10.1158/1078-0432.ccr-21-2092] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 08/19/2021] [Accepted: 08/19/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the gastrointestinal tract, with mutant succinate dehydrogenase (SDH) subunits (A-D) comprising less than 7.5% (i.e., 150-200/year) of new cases annually in the United States. Contrary to GISTs harboring KIT or PDGFRA mutations, SDH-mutant GISTs affect adolescents/young adults, often metastasize, and are frequently resistant to tyrosine kinase inhibitors (TKI). Lack of human models for any SDH-mutant tumors, including GIST, has limited molecular characterization and drug discovery. EXPERIMENTAL DESIGN We describe methods for establishing novel patient-derived SDH-mutant (mSDH) GIST models and interrogated the efficacy of temozolomide on these tumor models in vitro and in clinical trials of patients with mSDH GIST. RESULTS Molecular and metabolic characterization of our patient-derived mSDH GIST models revealed that these models recapitulate the transcriptional and metabolic hallmarks of parent tumors and SDH deficiency. We further demonstrate that temozolomide elicits DNA damage and apoptosis in our mSDH GIST models. Translating our in vitro discovery to the clinic, a cohort of patients with SDH-mutant GIST treated with temozolomide (n = 5) demonstrated a 40% objective response rate and 100% disease control rate, suggesting that temozolomide represents a promising therapy for this subset of GIST. CONCLUSIONS We report the first methods to establish patient-derived mSDH tumor models, which can be readily employed for understanding patient-specific tumor biology and treatment strategies. We also demonstrate that temozolomide is effective in patients with mSDH GIST who are refractory to existing chemotherapeutic drugs (namely, TKIs) in clinic for GISTs, bringing a promising treatment option for these patients to clinic.
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Affiliation(s)
- Mayra Yebra
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Surgery, Division of Surgical Oncology, University of California San Diego, San Diego, California
| | - Shruti Bhargava
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Surgery, Division of Surgical Oncology, University of California San Diego, San Diego, California
| | - Avi Kumar
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Bioengineering, University of California San Diego, La Jolla, California
| | - Adam M Burgoyne
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Medicine, Division of Hematology Oncology, University of California San Diego, San Diego, California
| | - Chih-Min Tang
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Surgery, Division of Surgical Oncology, University of California San Diego, San Diego, California
| | - Hyunho Yoon
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Surgery, Division of Surgical Oncology, University of California San Diego, San Diego, California
| | - Sudeep Banerjee
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Surgery, Division of Surgical Oncology, University of California San Diego, San Diego, California
| | - Joseph Aguilera
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Radiation Medicine and Applied Sciences, University of California San Diego, San Diego, California
| | - Thekla Cordes
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Bioengineering, University of California San Diego, La Jolla, California
| | - Vipul Sheth
- Department of Radiology, Stanford University, Palo Alto, Stanford, California
| | - Sangkyu Noh
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Surgery, Division of Surgical Oncology, University of California San Diego, San Diego, California
| | - Rowan Ustoy
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Surgery, Division of Surgical Oncology, University of California San Diego, San Diego, California
| | - Sam Li
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Surgery, Division of Surgical Oncology, University of California San Diego, San Diego, California
| | - Sunil J Advani
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Radiation Medicine and Applied Sciences, University of California San Diego, San Diego, California
| | | | - Michael C Heinrich
- Hematology/Medical Oncology, Portland VA Health Care System and OHSU Knight Cancer Institute, Portland, Oregon
| | - Razelle Kurzrock
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Medicine, Division of Hematology Oncology, University of California San Diego, San Diego, California.,Center for Personalized Cancer Therapy, University of California San Diego Moores Cancer Center, San Diego, California
| | - Scott M Lippman
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Medicine, Division of Hematology Oncology, University of California San Diego, San Diego, California.,Center for Personalized Cancer Therapy, University of California San Diego Moores Cancer Center, San Diego, California
| | - Paul T Fanta
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Medicine, Division of Hematology Oncology, University of California San Diego, San Diego, California.,Center for Personalized Cancer Therapy, University of California San Diego Moores Cancer Center, San Diego, California
| | - Olivier Harismendy
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Medicine, Division of Biomedical Informatics, University of California San Diego, San Diego, California
| | - Christian Metallo
- Moores Cancer Center, University of California San Diego, La Jolla, California.,Department of Bioengineering, University of California San Diego, La Jolla, California.,Diabetes and Endocrinology Research Center, University of California San Diego, La Jolla, California.,Institute of Engineering in Medicine, University of California San Diego, La Jolla, California
| | - Jason K Sicklick
- Moores Cancer Center, University of California San Diego, La Jolla, California. .,Department of Surgery, Division of Surgical Oncology, University of California San Diego, San Diego, California.,Center for Personalized Cancer Therapy, University of California San Diego Moores Cancer Center, San Diego, California
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15
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Pilco-Janeta DF, García-Valverde A, Gomez-Peregrina D, Serrano C. Emerging drugs for the treatment of gastrointestinal stromal tumors. Expert Opin Emerg Drugs 2021; 26:53-62. [PMID: 33645383 DOI: 10.1080/14728214.2021.1896704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
INTRODUCTION Oncogenic activation of KIT or PDGFRA receptor tyrosine kinases is the crucial event in gastrointestinal stromal tumor (GIST) biology. Seminal works during the past two decades have underscored, first, the continuous relevance of KIT/PDGFRA oncogenic signaling after progression to targeted inhibition; second, the heterogeneity of KIT/PDGFRA acquired mutations, that cannot be efficiently suppressed by any given tyrosine kinase inhibitor (TKI); and third, the presence of specific mutants highly resistant to all approved therapies. AREAS COVERED This review discusses treatment options in advanced/metastatic GIST, including a detailed dissection of ripretinib and avapritinib, the two novel small molecule inhibitors approved by the Food and Drug Administration in 2020. EXPERT OPINION The three only therapeutic options since 2012 for metastatic GIST patients were imatinib, sunitinib, and regorafenib. Although imatinib was highly effective in treatment-naïve GIST, the benefit of second- and third-line sunitinib and regorafenib was modest, thus emphasizing the medical need for new treatment options. Ripretinib, a switch control inhibitor with broad anti-KIT/PDGFRA activity, has been approved as ≥4th line in GIST after progression to all standard therapies. Avapritinib, a type I TKI highly specific against the multi-resistant PDGFRA D842V mutation, is approved in this specific subset of GIST patients.
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Affiliation(s)
- Daniel F Pilco-Janeta
- Sarcoma Translational Research Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Hospital Campus, Barcelona, Spain
| | - Alfonso García-Valverde
- Sarcoma Translational Research Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Hospital Campus, Barcelona, Spain
| | - David Gomez-Peregrina
- Sarcoma Translational Research Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Hospital Campus, Barcelona, Spain
| | - César Serrano
- Sarcoma Translational Research Laboratory, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Hospital Campus, Barcelona, Spain.,Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain
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16
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Liu M, Etherington MS, Hanna A, Medina BD, Vitiello GA, Bowler TG, Param NJ, Levin L, Rossi F, DeMatteo RP. Oncogenic KIT Modulates Type I IFN-Mediated Antitumor Immunity in GIST. Cancer Immunol Res 2021; 9:542-553. [PMID: 33648985 PMCID: PMC8102332 DOI: 10.1158/2326-6066.cir-20-0692] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 12/17/2020] [Accepted: 02/25/2021] [Indexed: 11/16/2022]
Abstract
Type I IFNs are implicated in tumor immunogenicity and response to systemic therapy, but their interaction with oncogene signaling is not well understood. Here, we studied oncogenic KIT, which drives gastrointestinal stromal tumor (GIST), the most common sarcoma. Using mouse models of GIST, we found that KIT inhibition reduced type I IFN production and signaling, which downregulated tumor MHC class I expression. Absence of type I IFN signaling increased tumor size, in part due to CD8+ T-cell impairment. Oncogenic KIT was required for GIST type I IFN signal transduction via STAT1. In human GIST cell lines and surgical specimens, type I IFN signaling contributed to human lymphocyte antigen class I expression and correlated with tumor immunogenicity. Augmenting the type I IFN response partially compensated for the immunosuppressive effects of KIT inhibition. Thus, KIT signaling contributes to type I IFN signaling, whereas KIT inhibition attenuates tumor immunogenicity and is partly rescued by innate immune stimulation.See related Spotlight on p. 489.
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Affiliation(s)
- Mengyuan Liu
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Mark S Etherington
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Andrew Hanna
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Benjamin D Medina
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Gerardo A Vitiello
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Timothy G Bowler
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Nesteene J Param
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Lillian Levin
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Ferdinand Rossi
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Ronald P DeMatteo
- Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.
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17
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Sakane T, Sakamoto Y, Masaki A, Murase T, Okuda K, Nakanishi R, Inagaki H. Mutation Profile of Thymic Carcinoma and Thymic Neuroendocrine Tumor by Targeted Next-generation Sequencing. Clin Lung Cancer 2020; 22:92-99.e4. [PMID: 33414055 DOI: 10.1016/j.cllc.2020.11.010] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 11/02/2020] [Accepted: 11/17/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Thymic carcinoma is a rare mediastinal neoplasm, and little is known about its genetic variability, which has hampered the development of targeted therapies. PATIENTS AND METHODS We tested a next-generation sequencing panel containing 50 common cancer-related genes in 48 cases of thymic carcinoma and 6 cases of thymic neuroendocrine tumor. RESULTS We detected 42 variant calls in 21 of 54 cases. There was no significant difference in mutation frequency between thymic carcinoma and thymic neuroendocrine tumors. Among these, TP53 was the most frequently mutated gene (18.5%), followed by KIT (7.4%) and PDGFRA (5.6%). According to the gene pathways and groups, the p53 pathway, including TP53 and ATM, was most frequently affected (20.4%), followed by the receptor tyrosine kinase (RTK)/RAS pathway (18.5%) and PI3K pathway (5.6%). According to the OncoKB, an expert-guided precision oncology knowledge base, 7 genes among 10 cases (18.5%) were annotated with level 1 evidence, suggesting potentially therapeutic targets. Prognostic analyses, conducted in thymic squamous cell carcinomas, revealed that tumor cases harboring gene mutations in RTKs, including KIT (7.4%), PDGFRA (5.6%) and EGFR (3.7%), were significantly associated with a worse overall survival time (P = .0481). Among clinicopathologic factors, the advanced Masaoka stage was marginally associated with a worse overall survival (P = .0757). In the subsequent multivariate analysis, neither of the factors achieved statistical significance. CONCLUSIONS In this preliminary next-generation sequencing study, we unexpectedly found evidence suggesting that several gene mutations might be therapeutic targets. The gene mutations in RTKs may be a valuable prognostic factor in thymic squamous cell carcinoma.
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Affiliation(s)
- Tadashi Sakane
- Department of Pathology and Molecular Diagnostics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; Department of Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yuma Sakamoto
- Department of Pathology and Molecular Diagnostics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Ayako Masaki
- Department of Pathology and Molecular Diagnostics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Takayuki Murase
- Department of Pathology and Molecular Diagnostics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Katsuhiro Okuda
- Department of Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Ryoichi Nakanishi
- Department of Oncology, Immunology and Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Hiroshi Inagaki
- Department of Pathology and Molecular Diagnostics, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
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18
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The V654A second-site KIT mutation increases tumor oncogenesis and STAT activation in a mouse model of gastrointestinal stromal tumor. Oncogene 2020; 39:7153-7165. [PMID: 33024275 PMCID: PMC7718339 DOI: 10.1038/s41388-020-01489-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 09/19/2020] [Accepted: 09/24/2020] [Indexed: 01/02/2023]
Abstract
Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and arises in the gastrointestinal tract. Most GISTs are caused by activating mutations in the KIT receptor tyrosine kinase, such as the exon 11 KIT V559Δ mutation. The small molecule imatinib inhibits KIT and has been a mainstay of therapy in GIST. Unfortunately, imatinib-treated patients typically relapse, most often due to clonal emergence of the resistance-associated KIT V654A mutation. To determine the biologic impact of this second-site mutation in vivo, we created a mouse model with the corresponding V558Δ;V653A Kit double mutation restricted (a) spatially to ETV1+ cells, which include the interstitial cells of Cajal (ICCs) from which GISTs presumably originate, and (b) temporally through tamoxifen treatment after birth. This resulted in the first in vivo model of the most common second-site mutation associated with imatinib resistance in GIST and the first in vivo demonstration that cell-autonomous expression of mutant KIT in the ICC lineage leads to GIST. GISTs driven by the V558Δ;V653A Kit double mutation were resistant to imatinib, while cabozantinib was more effective in overcoming resistance than sunitinib. Compared to control mice with a single V558Δ Kit mutation, mice with a double V558Δ; V653A Kit mutation had increased tumor oncogenesis and associated KIT-dependent STAT activation. Our findings demonstrate that the biologic consequences of a second-site mutation in an oncogenic driver may include not only a mechanism for drug resistance, but changes in tumor oncogenic potential and differential activation of signaling pathways.
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19
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Castel P, Rauen KA, McCormick F. The duality of human oncoproteins: drivers of cancer and congenital disorders. Nat Rev Cancer 2020; 20:383-397. [PMID: 32341551 PMCID: PMC7787056 DOI: 10.1038/s41568-020-0256-z] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/20/2020] [Indexed: 01/29/2023]
Abstract
Human oncoproteins promote transformation of cells into tumours by dysregulating the signalling pathways that are involved in cell growth, proliferation and death. Although oncoproteins were discovered many years ago and have been widely studied in the context of cancer, the recent use of high-throughput sequencing techniques has led to the identification of cancer-associated mutations in other conditions, including many congenital disorders. These syndromes offer an opportunity to study oncoprotein signalling and its biology in the absence of additional driver or passenger mutations, as a result of their monogenic nature. Moreover, their expression in multiple tissue lineages provides insight into the biology of the proto-oncoprotein at the physiological level, in both transformed and unaffected tissues. Given the recent paradigm shift in regard to how oncoproteins promote transformation, we review the fundamentals of genetics, signalling and pathogenesis underlying oncoprotein duality.
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Affiliation(s)
- Pau Castel
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
| | - Katherine A Rauen
- MIND Institute, Department of Pediatrics, University of California, Davis, Sacramento, CA, USA
| | - Frank McCormick
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA
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20
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Janardhan KS, Venkannagari P, Jensen H, Hoenerhoff MJ, Herbert RA, Malarkey DE, Sills RC, Pandiri AR. Do GISTs Occur in Rats and Mice? Immunohistochemical Characterization of Gastrointestinal Tumors Diagnosed as Smooth Muscle Tumors in The National Toxicology Program. Toxicol Pathol 2019; 47:577-584. [PMID: 31064278 DOI: 10.1177/0192623319845838] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
The majority of the tumors in the gastrointestinal (GI) tract of rats and mice, with spindle cell morphology, are diagnosed as smooth muscle tumors (SMTs). Similarly, several decades ago human GI tumors with spindle cell morphology were also diagnosed as SMTs. However, later investigations identified most of these tumors in humans as gastrointestinal stromal tumors (GISTs). The GISTs are considered to arise from the interstitial cells of Cajal located throughout the GI tract. Positive immunohistochemical staining with CKIT antibody is a well-accepted diagnostic marker for GISTs in humans. Since there is a considerable overlap between the histomorphology of SMTs and GISTs, it is not possible to distinguish them on hematoxylin and eosin stained sections. As a result, GISTs are not routinely diagnosed in toxicological studies. The current study was designed to evaluate the tumors diagnosed as leiomyoma or leiomyosarcoma in the National Toxicology Program's 2-year bioassays using CKIT, smooth muscle actin, and desmin immunohistochemistry. The results demonstrate that most of the mouse SMTs diagnosed as leiomyoma or leiomyosarcoma are likely GISTs, whereas in rats the tumors are likely SMTs and not GISTs.
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Affiliation(s)
| | - Priyanka Venkannagari
- 2 Division of National Toxicology Program, Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA. Venkannagari is now with the Bain and Company Inc, Boston, MA, USA. Mark is now with the Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Heather Jensen
- 2 Division of National Toxicology Program, Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA. Venkannagari is now with the Bain and Company Inc, Boston, MA, USA. Mark is now with the Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Mark J Hoenerhoff
- 2 Division of National Toxicology Program, Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA. Venkannagari is now with the Bain and Company Inc, Boston, MA, USA. Mark is now with the Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Ronald A Herbert
- 2 Division of National Toxicology Program, Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA. Venkannagari is now with the Bain and Company Inc, Boston, MA, USA. Mark is now with the Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - David E Malarkey
- 2 Division of National Toxicology Program, Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA. Venkannagari is now with the Bain and Company Inc, Boston, MA, USA. Mark is now with the Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Robert C Sills
- 2 Division of National Toxicology Program, Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA. Venkannagari is now with the Bain and Company Inc, Boston, MA, USA. Mark is now with the Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Arun R Pandiri
- 2 Division of National Toxicology Program, Cellular and Molecular Pathology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA. Venkannagari is now with the Bain and Company Inc, Boston, MA, USA. Mark is now with the Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI, USA
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21
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Vitiello GA, Bowler TG, Liu M, Medina BD, Zhang JQ, Param NJ, Loo JK, Goldfeder RL, Chibon F, Rossi F, Zeng S, DeMatteo RP. Differential immune profiles distinguish the mutational subtypes of gastrointestinal stromal tumor. J Clin Invest 2019; 129:1863-1877. [PMID: 30762585 PMCID: PMC6486334 DOI: 10.1172/jci124108] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Gastrointestinal stromal tumor (GIST) is the most common human sarcoma, frequently characterized by an oncogenic mutation in the KIT or platelet-derived growth factor receptor alpha (PDGFRA) genes. We performed RNA sequencing of 75 human GIST tumors from 75 patients, comprising the largest cohort of GISTs sequenced to date, in order to discover differences in the immune infiltrates of KIT and PDGFRA-mutant GIST. Through bioinformatics, immunohistochemistry, and flow cytometry, we found that PDGFRA-mutant GISTs harbored more immune cells with increased cytolytic activity when compared to KIT-mutant GISTs. PDGFRA-mutant GISTs expressed many chemokines, such as CXCL14, at a significantly higher level when compared to KIT-mutant GISTs and exhibited more diverse driver-derived neoepitope:HLA binding, both of which may contribute to PDGFRA-mutant GIST immunogenicity. Through machine learning, we generated gene expression-based immune profiles capable of differentiating KIT and PDGFRA-mutant GISTs, and also identified additional immune features of high PD-1 and PD-L1 expressing tumors across all GIST mutational subtypes, which may provide insight into immunotherapeutic opportunities and limitations in GIST.
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Affiliation(s)
| | - Timothy G. Bowler
- Department of Medicine, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA
| | - Mengyuan Liu
- Department of Surgery and
- Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | | | | | - Nesteene J. Param
- Department of Surgery and
- Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | | | - Rachel L. Goldfeder
- Genome Technologies, The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA
| | - Frederic Chibon
- INSERM U1037, Cancer Research Center of Toulouse, Toulouse, France
| | - Ferdinand Rossi
- Department of Surgery and
- Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | | | - Ronald P. DeMatteo
- Department of Surgery and
- Department of Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, USA
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22
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Medina BD, Liu M, Vitiello GA, Seifert AM, Zeng S, Bowler T, Zhang JQ, Cavnar MJ, Loo JK, Param NJ, Maltbaek JH, Rossi F, Balachandran V, DeMatteo RP. Oncogenic kinase inhibition limits Batf3-dependent dendritic cell development and antitumor immunity. J Exp Med 2019; 216:1359-1376. [PMID: 31000683 PMCID: PMC6547861 DOI: 10.1084/jem.20180660] [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: 04/08/2018] [Revised: 02/22/2019] [Accepted: 04/03/2019] [Indexed: 12/12/2022] Open
Abstract
Medina et al. demonstrate that Kit oncogene activity in gastrointestinal stromal tumor modulates the CD103+CD11b− dendritic cell (DC) lineage. The antitumor efficacy of oncogene inhibition initially depends on preexisting immunity orchestrated by CD103+CD11b− DCs, but subsequently is limited by a decrease in DC lineage maturation. Gastrointestinal stromal tumor (GIST) is driven by an activating mutation in the KIT proto-oncogene. Using a mouse model of GIST and human specimens, we show that intratumoral murine CD103+CD11b− dendritic cells (DCs) and human CD141+ DCs are associated with CD8+ T cell infiltration and differentiation. In mice, the antitumor effect of the Kit inhibitor imatinib is partially mediated by CD103+CD11b− DCs, and effector CD8+ T cells initially proliferate. However, in both mice and humans, chronic imatinib therapy decreases intratumoral DCs and effector CD8+ T cells. The mechanism in our mouse model depends on Kit inhibition, which reduces intratumoral GM-CSF, leading to the accumulation of Batf3-lineage DC progenitors. GM-CSF is produced by γδ T cells via macrophage IL-1β. Stimulants that expand and mature DCs during imatinib treatment improve antitumor immunity. Our findings identify the importance of tumor cell oncogene activity in modulating the Batf3-dependent DC lineage and reveal therapeutic limitations for combined checkpoint blockade and tyrosine kinase inhibition.
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Affiliation(s)
- Benjamin D Medina
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY
| | - Mengyuan Liu
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY.,Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA
| | - Gerardo A Vitiello
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY
| | - Adrian M Seifert
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY
| | - Shan Zeng
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY
| | - Timothy Bowler
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY
| | - Jennifer Q Zhang
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY
| | - Michael J Cavnar
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY
| | - Jennifer K Loo
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY
| | - Nesteene J Param
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY
| | - Joanna H Maltbaek
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY
| | - Ferdinand Rossi
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY
| | - Vinod Balachandran
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY
| | - Ronald P DeMatteo
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY .,Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA
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23
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Settas N, Faucz FR, Stratakis CA. Succinate dehydrogenase (SDH) deficiency, Carney triad and the epigenome. Mol Cell Endocrinol 2018; 469:107-111. [PMID: 28739378 PMCID: PMC5776069 DOI: 10.1016/j.mce.2017.07.018] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2017] [Revised: 07/13/2017] [Accepted: 07/20/2017] [Indexed: 12/29/2022]
Abstract
In this report, we review the relationship between succinate dehydrogenase (SDH) deficiency and the epigenome, especially with regards to two clinical conditions. Carney triad (CT) is a very rare disease with synchronous or metachronous occurrence of at least three different tumor entities; gastric gastrointestinal stromal tumor (GIST), paraganglioma (PGL), and pulmonary chondroma. This condition affects mostly females and it is never inherited. Another disease that shares two of the tumor components of CT, namely GIST and PGL is the Carney-Stratakis syndrome (CSS) or dyad. CSS affects both genders during childhood and adolescence. We review herein the main clinical features and molecular mechanisms behind those two syndromes that share quite a bit of similarities, but one is non-hereditary (CT) whereas the other shows an autosomal-dominant, with incomplete penetrance, inheritance pattern (CSS). Both CT and CSS are caused by the deficiency of the succinate dehydrogenase (SDH) enzyme. The key difference between the two syndromes is the molecular mechanism that causes the SDH deficiency. Most cases of CT show down-regulation of SDH through site-specific hyper-methylation of the SDHC gene, whereas CSS cases carry inactivating germline mutations within one of the genes coding for the SDH subunits A, B, C, or D (SDHA, SDHB, SDHC, and SDHD). There is only partial overlap between the two conditions (there are a few patients with CT that have SDH subunit mutations) but both lead to increased methylation of the entire genome in the tumors associated with them. Other tumors (outside CT and CSS) that have SDH deficiency are associated with increased methylation of the entire genome, but only in CT there is site-specific methylation of the SDHC gene. These findings have implications for diagnostics and the treatment of patients with these, often metastatic tumors.
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Affiliation(s)
- Nikolaos Settas
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, USA.
| | - Fabio R Faucz
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, USA
| | - Constantine A Stratakis
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, USA
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24
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Zhang JQ, Zeng S, Vitiello GA, Seifert AM, Medina BD, Beckman MJ, Loo JK, Santamaria-Barria J, Maltbaek JH, Param NJ, Moral JA, Zhao JN, Balachandran V, Rossi F, Antonescu CR, DeMatteo RP. Macrophages and CD8 + T Cells Mediate the Antitumor Efficacy of Combined CD40 Ligation and Imatinib Therapy in Gastrointestinal Stromal Tumors. Cancer Immunol Res 2018; 6:434-447. [PMID: 29467128 DOI: 10.1158/2326-6066.cir-17-0345] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2017] [Revised: 11/10/2017] [Accepted: 02/16/2018] [Indexed: 11/16/2022]
Abstract
Tyrosine kinase inhibition of gastrointestinal stromal tumors (GIST) is effective but typically culminates in resistance and is rarely curative. Immunotherapy has potential application to GIST, as we previously showed that T-cell checkpoint blockade increases the antitumor effects of imatinib. Here, we showed that ligation of CD40 using an agonistic antibody (anti-CD40) activated tumor-associated macrophages (TAMs) in vivo in a knock-in mouse model of GIST harboring a germline mutation in Kit exon 11. Activated TAMs had greater TNFα production and NFκB signaling and directly inhibited tumor cells in vitro Anti-CD40 required concomitant therapy with imatinib for efficacy and depended on TAMs, and to a lesser extent CD8+ T cells, but not on CD4+ T cells or B cells. In an analysis of 50 human GIST specimens by flow cytometry, we found that CD40 was expressed on human TAMs and tumor cells yet was downregulated after response to imatinib. CD40 ligation did not have a direct inhibitory effect on human GIST cells. Our findings provide the rationale for combining anti-CD40 and tyrosine kinase inhibition to treat human GIST. Cancer Immunol Res; 6(4); 434-47. ©2018 AACR.
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Affiliation(s)
- Jennifer Q Zhang
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Shan Zeng
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Gerardo A Vitiello
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Adrian M Seifert
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Benjamin D Medina
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Michael J Beckman
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jennifer K Loo
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | | | - Joanna H Maltbaek
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Nesteene J Param
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - John A Moral
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Julia N Zhao
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Vinod Balachandran
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ferdinand Rossi
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Cristina R Antonescu
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ronald P DeMatteo
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York. .,Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
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25
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Taddei A, Castiglione F, Degl'Innocenti DR, Buccoliero AM, Garbini F, Tommasi C, Freschi G, Bechi P, Messerini L, Taddei GL. NF2 Expression Levels of Gastrointestinal Stromal Tumors: A Quantitative Real-Time PCR Study. TUMORI JOURNAL 2018; 94:551-5. [DOI: 10.1177/030089160809400417] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Gastrointestinal stromal tumors are the most common mesenchymal tumors of the gastrointestinal tract. Until today, there have been few markers specific for the tumor. This has complicated the differential diagnosis of the neoplasm from tumors of smooth muscle origin. Recently, the proto-oncogene c-kit has been shown to be a very relevant marker as it almost invariably is expressed in gastrointestinal stromal tumors. Radiation exposure, hormonal and genetic factors, particularly neurofibromatosis 2, have been implicated in their development and growth. GIST initiation, either in NF2-associated or in sporadic cases, is linked to inactivation of members of the proteins 4.1 superfamily. The majority of the mutations identified in the NF2 gene result in a truncated protein and are clinically associated with a severe phenotype. Occasionally, missense mutations associated with a mild phenotype may occur. We compared NF2 gene expression in 5 cases with gastrointestinal stromal tumors by quantitative real-time polymerase chain reaction analysis. NF2 gene mRNA expression was assessed in fresh tissue of stomach from 5 consecutive patients. We detected no alterations in NF2 gene expression in the quantitative analyses of the 5 tumors.
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Affiliation(s)
- Antonio Taddei
- Department of Surgical Pathology, University of Florence, School of Medicine, Florence, Italy
| | - Francesca Castiglione
- Department of Human Pathology and Oncology, University of Florence, School of Medicine, Florence, Italy
| | | | - Anna Maria Buccoliero
- Department of Human Pathology and Oncology, University of Florence, School of Medicine, Florence, Italy
| | - Francesca Garbini
- Department of Human Pathology and Oncology, University of Florence, School of Medicine, Florence, Italy
| | - Cinzia Tommasi
- Department of Surgical Pathology, University of Florence, School of Medicine, Florence, Italy
| | - Giancarlo Freschi
- Department of Surgical Pathology, University of Florence, School of Medicine, Florence, Italy
| | - Paolo Bechi
- Department of Surgical Pathology, University of Florence, School of Medicine, Florence, Italy
| | - Luca Messerini
- Department of Surgical Pathology, University of Florence, School of Medicine, Florence, Italy
| | - Gian Luigi Taddei
- Department of Surgical Pathology, University of Florence, School of Medicine, Florence, Italy
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26
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Sarmiento R, Bonginelli P, Cacciamani F, Salerno F, Gasparini G. Gastrointestinal Stromal Tumors (GISTs): From Science to Targeted Therapy. Int J Biol Markers 2018; 23:96-110. [DOI: 10.1177/172460080802300206] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. GISTs represent a distinct category of tumors characterized by oncogenic mutations of the KIT receptor tyrosine kinase in a majority of patients. KIT is useful not only for the diagnosis but also for targeted therapy of this disease. Imatinib, a tyrosine kinase inhibitor, is widely used in advanced and metastatic GISTs. This agent revolutionized the treatment strategy of advanced disease and is being tested in the neoadjuvant and adjuvant settings with encouraging results. New therapeutic agents like sunitinib have now been approved, enriching the treatment scenario for imatinib-resistant GISTs. The present review reports on the peculiar characteristics of this disease through its biology and molecular patterns, focusing on the predictive value of KIT mutations and their correlation with clinical outcome as well as on the activity of and resistance to approved targeted drugs.
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Affiliation(s)
- R. Sarmiento
- Division of Medical Oncology, San Filippo Neri Hospital, Rome - Italy
| | - P. Bonginelli
- Division of Medical Oncology, San Filippo Neri Hospital, Rome - Italy
| | - F. Cacciamani
- Division of Medical Oncology, San Filippo Neri Hospital, Rome - Italy
| | - F. Salerno
- Division of Medical Oncology, San Filippo Neri Hospital, Rome - Italy
| | - G. Gasparini
- Division of Medical Oncology, San Filippo Neri Hospital, Rome - Italy
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27
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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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28
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Vitiello GA, Medina BD, Zeng S, Bowler TG, Zhang JQ, Loo JK, Param NJ, Liu M, Moral AJ, Zhao JN, Rossi F, Antonescu CR, Balachandran VP, Cross JR, DeMatteo RP. Mitochondrial Inhibition Augments the Efficacy of Imatinib by Resetting the Metabolic Phenotype of Gastrointestinal Stromal Tumor. Clin Cancer Res 2017; 24:972-984. [PMID: 29246941 DOI: 10.1158/1078-0432.ccr-17-2697] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Revised: 11/10/2017] [Accepted: 12/05/2017] [Indexed: 12/14/2022]
Abstract
Purpose: Imatinib dramatically reduces gastrointestinal stromal tumor (GIST) 18F-FDG uptake, providing an early indicator of treatment response. Despite decreased glucose internalization, many GIST cells persist, suggesting that alternative metabolic pathways are used for survival. The role of mitochondria in imatinib-treated GIST is largely unknown.Experimental Design: We quantified the metabolic activity of several human GIST cell lines. We treated human GIST xenografts and genetically engineered KitV558del/+ mice with the mitochondrial oxidative phosphorylation inhibitor VLX600 in combination with imatinib and analyzed tumor volume, weight, histology, molecular signaling, and cell cycle activity. In vitro assays on human GIST cell lines were also performed.Results: Imatinib therapy decreased glucose uptake and downstream glycolytic activity in GIST-T1 and HG129 cells by approximately half and upregulated mitochondrial enzymes and improved mitochondrial respiratory capacity. Mitochondrial inhibition with VLX600 had a direct antitumor effect in vitro while appearing to promote glycolysis through increased AKT signaling and glucose transporter expression. When combined with imatinib, VLX600 prevented imatinib-induced cell cycle escape and reduced p27 expression, leading to increased apoptosis when compared to imatinib alone. In KitV558del/+ mice, VLX600 alone did not induce tumor cell death, but had a profound antitumor effect when combined with imatinib.Conclusions: Our findings show that imatinib alters the metabolic phenotype of GIST, and this may contribute to imatinib resistance. Our work offers preclinical proof of concept of metabolic targeting as an effective strategy for the treatment of GIST. Clin Cancer Res; 24(4); 972-84. ©2017 AACR.
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Affiliation(s)
- Gerardo A Vitiello
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Benjamin D Medina
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Shan Zeng
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Timothy G Bowler
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jennifer Q Zhang
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jennifer K Loo
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Nesteene J Param
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Mengyuan Liu
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Alec J Moral
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Julia N Zhao
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ferdinand Rossi
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Cristina R Antonescu
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Vinod P Balachandran
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Justin R Cross
- The Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ronald P DeMatteo
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
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29
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Ran L, Chen Y, Sher J, Wong EWP, Murphy D, Zhang JQ, Li D, Deniz K, Sirota I, Cao Z, Wang S, Guan Y, Shukla S, Li KY, Chramiec A, Xie Y, Zheng D, Koche RP, Antonescu CR, Chen Y, Chi P. FOXF1 Defines the Core-Regulatory Circuitry in Gastrointestinal Stromal Tumor. Cancer Discov 2017; 8:234-251. [PMID: 29162563 DOI: 10.1158/2159-8290.cd-17-0468] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 09/26/2017] [Accepted: 11/14/2017] [Indexed: 01/04/2023]
Abstract
The cellular context that integrates upstream signaling and downstream nuclear response dictates the oncogenic behavior and shapes treatment responses in distinct cancer types. Here, we uncover that in gastrointestinal stromal tumor (GIST), the forkhead family member FOXF1 directly controls the transcription of two master regulators, KIT and ETV1, both required for GIST precursor-interstitial cells of Cajal lineage specification and GIST tumorigenesis. Further, FOXF1 colocalizes with ETV1 at enhancers and functions as a pioneer factor that regulates the ETV1-dependent GIST lineage-specific transcriptome through modulation of the local chromatin context, including chromatin accessibility, enhancer maintenance, and ETV1 binding. Functionally, FOXF1 is required for human GIST cell growth in vitro and murine GIST tumor growth and maintenance in vivo The simultaneous control of the upstream signaling and nuclear response sets up a unique regulatory paradigm and highlights the critical role of FOXF1 in enforcing the GIST cellular context for highly lineage-restricted clinical behavior and treatment response.Significance: We uncover that FOXF1 defines the core-regulatory circuitry in GIST through both direct transcriptional regulation and pioneer factor function. The unique and simultaneous control of signaling and transcriptional circuitry by FOXF1 sets up an enforced transcriptional addiction to FOXF1 in GIST, which can be exploited diagnostically and therapeutically. Cancer Discov; 8(2); 234-51. ©2017 AACR.See related commentary by Lee and Duensing, p. 146This article is highlighted in the In This Issue feature, p. 127.
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Affiliation(s)
- Leili Ran
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Yuedan Chen
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, New York
| | - Jessica Sher
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Elissa W P Wong
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Devan Murphy
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jenny Q Zhang
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Dan Li
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Kemal Deniz
- Department of Pathology, Erciyes University, Kayseri, Turkey
| | - Inna Sirota
- Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York
| | - Zhen Cao
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, New York
| | - Shangqian Wang
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Youxin Guan
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Shipra Shukla
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Katie Yang Li
- Center of Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Alan Chramiec
- Center of Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York.,Biomedical Engineering, Columbia University, New York, New York
| | - Yuanyuan Xie
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Deyou Zheng
- Department of Genetics, Albert Einstein College of Medicine, Bronx, New York.,Department of Neurology, Albert Einstein College of Medicine, Bronx, New York.,Department of Neuroscience, Albert Einstein College of Medicine, Bronx, New York
| | - Richard P Koche
- Center of Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Cristina R Antonescu
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Yu Chen
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. .,Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, New York.,Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.,Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Ping Chi
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. .,Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, New York.,Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.,Department of Medicine, Weill Cornell Medical College, New York, New York
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30
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Charville GW, Longacre TA. Surgical Pathology of Gastrointestinal Stromal Tumors: Practical Implications of Morphologic and Molecular Heterogeneity for Precision Medicine. Adv Anat Pathol 2017; 24:336-353. [PMID: 28820749 DOI: 10.1097/pap.0000000000000166] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Gastrointestinal stromal tumor (GIST), the most common mesenchymal neoplasm of the gastrointestinal tract, exhibits diverse histologic and clinical manifestations. With its putative origin in the gastrointestinal pacemaker cell of Cajal, GIST can arise in association with any portion of the tubular gastrointestinal tract. Morphologically, GISTs are classified as spindled or epithelioid, though each of these subtypes encompasses a broad spectrum of microscopic appearances, many of which mimic other histologic entities. Despite this morphologic ambiguity, the diagnosis of GIST is aided in many cases by immunohistochemical detection of KIT (CD117) or DOG1 expression. The natural history of GIST ranges from that of a tumor cured by surgical resection to that of a locally advanced or even widely metastatic, and ultimately fatal, disease. This clinicopathologic heterogeneity is paralleled by an underlying molecular diversity: the majority of GISTs are associated with spontaneous activating mutations in KIT, PDGFRA, or BRAF, while additional subsets are driven by genetic lesions-often inherited-of NF1 or components of the succinate dehydrogenase enzymatic complex. Specific gene mutations correlate with particular anatomic or morphologic characteristics and, in turn, with distinct clinical behaviors. Therefore, prognostication and treatment are increasingly dictated not only by morphologic clues, but also by accompanying molecular genetic features. In this review, we provide a comprehensive description of the heterogenous molecular underpinnings of GIST, including implications for the practicing pathologist with regard to morphologic identification, immunohistochemical diagnosis, and clinical management.
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31
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Direct engagement of the PI3K pathway by mutant KIT dominates oncogenic signaling in gastrointestinal stromal tumor. Proc Natl Acad Sci U S A 2017; 114:E8448-E8457. [PMID: 28923937 DOI: 10.1073/pnas.1711449114] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) predominantly harbor activating mutations in the receptor tyrosine kinase KIT. To genetically dissect in vivo the requirement of different signal transduction pathways emanating from KIT for tumorigenesis, the oncogenic KitV558Δ mutation was combined with point mutations abrogating specific phosphorylation sites on KIT. Compared with single-mutant KitV558Δ/+ mice, double-mutant KitV558Δ;Y567F/Y567F knock-in mice lacking the SRC family kinase-binding site on KIT (pY567) exhibited attenuated MAPK signaling and tumor growth. Surprisingly, abrogation of the PI3K-binding site (pY719) in KitV558Δ;Y719F/Y719F mice prevented GIST development, although the interstitial cells of Cajal (ICC), the cells of origin of GIST, were normal. Pharmacologic inhibition of the PI3K pathway in tumor-bearing KitV558Δ/+ mice with the dual PI3K/mTOR inhibitor voxtalisib, the pan-PI3K inhibitor pilaralisib, and the PI3K-alpha-restricted inhibitor alpelisib each diminished tumor proliferation. The addition of the MEK inhibitor PD-325901 or binimetinib further decreased downstream KIT signaling. Moreover, combining PI3K and MEK inhibition was effective against imatinib-resistant KitV558Δ;T669I/+ tumors.
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32
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SCF-KIT signaling induces endothelin-3 synthesis and secretion: Thereby activates and regulates endothelin-B-receptor for generating temporally- and spatially-precise nitric oxide to modulate SCF- and or KIT-expressing cell functions. PLoS One 2017; 12:e0184154. [PMID: 28880927 PMCID: PMC5589172 DOI: 10.1371/journal.pone.0184154] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Accepted: 08/19/2017] [Indexed: 01/11/2023] Open
Abstract
We demonstrate that SCF-KIT signaling induces synthesis and secretion of endothelin-3 (ET3) in human umbilical vein endothelial cells and melanoma cells in vitro, gastrointestinal stromal tumors, human sun-exposed skin, and myenteric plexus of human colon post-fasting in vivo. This is the first report of a physiological mechanism of ET3 induction. Integrating our finding with supporting data from literature leads us to discover a previously unreported pathway of nitric oxide (NO) generation derived from physiological endothelial NO synthase (eNOS) or neuronal NOS (nNOS) activation (referred to as the KIT-ET3-NO pathway). It involves: (1) SCF-expressing cells communicate with neighboring KIT-expressing cells directly or indirectly (cleaved soluble SCF). (2) SCF-KIT signaling induces timely local ET3 synthesis and secretion. (3) ET3 binds to ETBR on both sides of intercellular space. (4) ET3-binding-initiated-ETBR activation increases cytosolic Ca2+, activates cell-specific eNOS or nNOS. (5) Temporally- and spatially-precise NO generation. NO diffuses into neighboring cells, thus acts in both SCF- and KIT-expressing cells. (6) NO modulates diverse cell-specific functions by NO/cGMP pathway, controlling transcriptional factors, or other mechanisms. We demonstrate the critical physiological role of the KIT-ET3-NO pathway in fulfilling high demand (exceeding basal level) of endothelium-dependent NO generation for coping with atherosclerosis, pregnancy, and aging. The KIT-ET3-NO pathway most likely also play critical roles in other cell functions that involve dual requirement of SCF-KIT signaling and NO. New strategies (e.g. enhancing the KIT-ET3-NO pathway) to harness the benefit of endogenous eNOS and nNOS activation and precise NO generation for correcting pathophysiology and restoring functions warrant investigation.
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33
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34
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Ran L, Murphy D, Sher J, Cao Z, Wang S, Walczak E, Guan Y, Xie Y, Shukla S, Zhan Y, Antonescu CR, Chen Y, Chi P. ETV1-Positive Cells Give Rise to BRAFV600E -Mutant Gastrointestinal Stromal Tumors. Cancer Res 2017; 77:3758-3765. [PMID: 28539323 DOI: 10.1158/0008-5472.can-16-3510] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Revised: 03/09/2017] [Accepted: 05/19/2017] [Indexed: 12/29/2022]
Abstract
Gastrointestinal stromal tumor (GIST) is the most common subtype of sarcoma. Despite clinical advances in the treatment of KIT/PDGFRA-mutant GIST, similar progress against KIT/PDGFRA wild-type GIST, including mutant BRAF-driven tumors, has been limited by a lack of model systems. ETV1 is a master regulator in the intestinal cells of Cajal (ICC), thought to be the cells of origin of GIST. Here, we present a model in which the ETV1 promoter is used to specifically and inducibly drive Cre recombinase in ICC as a strategy to study GIST pathogenesis. Using a conditional allele for BrafV600E , a mutation observed in clinical cases of GIST, we observed that BrafV600E activation was sufficient to drive ICC hyperplasia but not GIST tumorigenesis. In contrast, combining BrafV600E activation with Trp53 loss was sufficient to drive both ICC hyperplasia and formation of multifocal GIST-like tumors in the mouse gastrointestinal tract with 100% penetrance. This mouse model of sporadic GIST model was amenable to therapeutic intervention, and it recapitulated clinical responses to RAF inhibition seen in human GIST. Our work offers a useful in vivo model of human sporadic forms of BRAF-mutant GIST to help unravel its pathogenesis and therapeutic response to novel experimental agents. Cancer Res; 77(14); 3758-65. ©2017 AACR.
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Affiliation(s)
- Leili Ran
- Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Devan Murphy
- School of Veterinary Medicine, University of California, Davis, California
| | - Jessica Sher
- Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Zhen Cao
- Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Shangqian Wang
- Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Edward Walczak
- Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Youxin Guan
- Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Yuanyuan Xie
- Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Shipra Shukla
- Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Yu Zhan
- Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Cristina R Antonescu
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Yu Chen
- Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York. .,Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.,Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Ping Chi
- Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York. .,Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.,Department of Medicine, Weill Cornell Medical College, New York, New York
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35
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Bannon AE, Klug LR, Corless CL, Heinrich MC. Using molecular diagnostic testing to personalize the treatment of patients with gastrointestinal stromal tumors. Expert Rev Mol Diagn 2017; 17:445-457. [PMID: 28317407 DOI: 10.1080/14737159.2017.1308826] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
INTRODUCTION The diagnosis and treatment of gastrointestinal stromal tumor (GIST) has emerged as a paradigm for modern cancer treatment ('precision medicine'), as it highlights the importance of matching molecular defects with specific therapies. Over the past two decades, the molecular classification and diagnostic work up of GIST has been radically transformed, accompanied by the development of molecular therapies for specific subgroups of GIST. This review summarizes the developments in the field of molecular diagnosis of GIST, particularly as they relate to optimizing medical therapy. Areas covered: Based on an extensive literature search of the molecular and clinical aspects of GIST, the authors review the most important developments in this field with an emphasis on the differential diagnosis of GIST including mutation testing, therapeutic implications of each molecular subtype, and emerging technologies relevant to the field. Expert commentary: The use of molecular diagnostics to classify GIST has been shown to be successful in optimizing patient treatment, but these methods remain under-utilized. In order to facilitate efficient and comprehensive molecular testing, the authors have developed a decision tree to aid clinicians.
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Affiliation(s)
- Amber E Bannon
- a Portland VA Health Care System and OHSU Knight Cancer Institute , Portland , OR , USA
| | - Lillian R Klug
- a Portland VA Health Care System and OHSU Knight Cancer Institute , Portland , OR , USA
| | - Christopher L Corless
- a Portland VA Health Care System and OHSU Knight Cancer Institute , Portland , OR , USA
| | - Michael C Heinrich
- a Portland VA Health Care System and OHSU Knight Cancer Institute , Portland , OR , USA
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36
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Abstract
Better diagnostic biomarkers and therapeutic options are still necessary for patients with sarcomas due to the current limitations of diagnosis and treatment. Exosomes are small extracellular membrane vesicles that are released by various cells and are found in most body fluids. Tumor-derived exosomes have been proven to mediate tumorigenesis, intercellular communication, microenvironment modulation, and metastasis in different cancers, including in sarcomas. Recently, exosomes have been considered as potential biomarkers for sarcoma diagnosis and prognosis, and as possible targets for sarcoma therapy. Moreover, due to their specific cell tropism and bioavailability, exosomes can also be engineered as vehicles for drug delivery. In this review, we discuss recent advances in the roles of tumor-derived exosomes in sarcoma and their potential clinical applications.
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37
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Lee A, Huang P, DeMatteo RP, Pollack SM. Immunotherapy for Soft Tissue Sarcoma: Tomorrow Is Only a Day Away. Am Soc Clin Oncol Educ Book 2017; 35:281-90. [PMID: 27249707 DOI: 10.1200/edbk_157439] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Despite the advances taking place for patients with many types of cancer, to date there has been little success in meeting the great need for novel treatments of advanced soft tissue sarcoma with effective immunologic therapies. Here, we review recent clinical and preclinical data that indicate immune responses against sarcomas occur spontaneously and can also be successfully provoked. Efforts to manipulate the sarcoma immune microenvironment have the potential to eradicate disease and may also sensitize tumors to other tumor-targeted immunotherapeutic approaches. Other approaches, including vaccines and genetic engineering of T cells, offer a promising opportunity to actively direct cytotoxic lymphocytes toward antigen-bearing sarcomas. Drawing parallels with recent advances made in other cancer types, we identify ways in which sarcomas can be included in the ongoing immunotherapy revolution.
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Affiliation(s)
- Alex Lee
- From the Department of Medical Oncology, Royal Marsden Hospital London, United Kingdom; Institute of Cancer Research, London, United Kingdom; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY; Fred Hutchinson Cancer Research Center, Division of Oncology, University of Washington, Seattle, WA
| | - Paul Huang
- From the Department of Medical Oncology, Royal Marsden Hospital London, United Kingdom; Institute of Cancer Research, London, United Kingdom; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY; Fred Hutchinson Cancer Research Center, Division of Oncology, University of Washington, Seattle, WA
| | - Ronald P DeMatteo
- From the Department of Medical Oncology, Royal Marsden Hospital London, United Kingdom; Institute of Cancer Research, London, United Kingdom; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY; Fred Hutchinson Cancer Research Center, Division of Oncology, University of Washington, Seattle, WA
| | - Seth M Pollack
- From the Department of Medical Oncology, Royal Marsden Hospital London, United Kingdom; Institute of Cancer Research, London, United Kingdom; Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY; Fred Hutchinson Cancer Research Center, Division of Oncology, University of Washington, Seattle, WA
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38
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Schmieder M, Henne-Bruns D, Mayer B, Knippschild U, Rolke C, Schwab M, Kramer K. Comparison of Different Risk Classification Systems in 558 Patients with Gastrointestinal Stromal Tumors after R0-Resection. Front Pharmacol 2016; 7:504. [PMID: 28082898 PMCID: PMC5187374 DOI: 10.3389/fphar.2016.00504] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Accepted: 12/07/2016] [Indexed: 12/12/2022] Open
Abstract
Background: Due to adjuvant treatment concepts for patients with R0-resected gastrointestinal stromal tumors (GIST), a reproducible and reliable risk classification system proved of utmost importance for optimal treatment of patients and prediction of prognosis. The aim of this study was to reevaluate the impact of five widely-applied and well-established GIST risk classification systems (i.e., scores by Fletcher, Miettinen, Huang, Joensuu, and TNM classification) on a series of 558 GIST patients with long-term follow-up after R0 resection. Methods: Tumor size, mitotic count and site were used in variable combination to predict high- and low risk patients by the use of the five risk classification models. For survival analyses disease-specific survival, disease-free survival and overall-survival were investigated. Patients with initial metastatic disease or incompletely resectable tumors were excluded. Results: All GIST classification models distinguished well between patients with high-risk and low-risk tumors and none of the five risk systems was superior to predict patient outcome. The models showed significant heterogeneity. There was no significant difference between the different risk-groups regarding overall-survival. Subdivision of GIST patients with very low- and low-risk appeared to be negligible. Conclusions: Currently applied GIST risk classification systems are comparable to predict high- or low-risk patients with initial non-metastatic and completely resected GIST. However, the heterogeneity of the high-risk group and the absence of differences in overall survival indicate the need for more precise tumor- and patient-related criteria for better stratification of GIST and identification of patients who would benefit best from adjuvant tyrosine kinase inhibitor therapy.
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Affiliation(s)
- Michael Schmieder
- Department of Internal Medicine, Alb-Fils-Kliniken Göppingen, Germany
| | - Doris Henne-Bruns
- Department of General and Visceral Surgery, University Hospital Ulm Ulm, Germany
| | - Benjamin Mayer
- Institute of Epidemiology and Medical Biometry, University of Ulm Ulm, Germany
| | - Uwe Knippschild
- Department of General and Visceral Surgery, University Hospital Ulm Ulm, Germany
| | - Claudia Rolke
- Department of General and Visceral Surgery, University Hospital Ulm Ulm, Germany
| | - Matthias Schwab
- Dr. Margarete Fischer-Bosch Institute of Clinical PharmacologyStuttgart, Germany; Department of Pharmacy and Biochemistry, University of TübingenTübingen, Germany; Department of Clinical Pharmacology, University Hospital TübingenTübingen, Germany
| | - Klaus Kramer
- Department of General and Visceral Surgery, University Hospital Ulm Ulm, Germany
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39
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Ke H, Kazi JU, Zhao H, Sun J. Germline mutations of KIT in gastrointestinal stromal tumor (GIST) and mastocytosis. Cell Biosci 2016; 6:55. [PMID: 27777718 PMCID: PMC5070372 DOI: 10.1186/s13578-016-0120-8] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2016] [Accepted: 10/04/2016] [Indexed: 01/01/2023] Open
Abstract
Somatic mutations of KIT are frequently found in mastocytosis and gastrointestinal stromal tumor (GIST), while germline mutations of KIT are rare, and only found in few cases of familial GIST and mastocytosis. Although ligand-independent activation is the common feature of KIT mutations, the phenotypes mediated by various germline KIT mutations are different. Germline KIT mutations affect different tissues such as interstitial cells of Cajal (ICC), mast cells or melanocytes, and thereby lead to GIST, mastocytosis, or abnormal pigmentation. In this review, we summarize germline KIT mutations in familial mastocytosis and GIST and discuss the possible cellular context dependent transforming activity of KIT mutations.
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Affiliation(s)
- Hengning Ke
- Department of Pathogen Biology and Immunology, School of Basic Medical Sciences, Ningxia Medical University, No. 1160 Shengli Street, Yinchuan, 750004 People's Republic of China ; Translational Cancer Lab, General Hospital of Ningxia Medical University, Yinchuan, People's Republic of China
| | - Julhash U Kazi
- Division of Translational Cancer Research, Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden
| | - Hui Zhao
- Faculty of Medicine, School of Biomedical Sciences, The Chinese University of Hong Kong, Sha Tin, Hong Kong, People's Republic of China
| | - Jianmin Sun
- Department of Pathogen Biology and Immunology, School of Basic Medical Sciences, Ningxia Medical University, No. 1160 Shengli Street, Yinchuan, 750004 People's Republic of China ; Division of Translational Cancer Research, Lund Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund, Sweden
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40
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Seifert AM, Zeng S, Zhang JQ, Kim TS, Cohen NA, Beckman MJ, Medina BD, Maltbaek JH, Loo JK, Crawley MH, Rossi F, Besmer P, Antonescu CR, DeMatteo RP. PD-1/PD-L1 Blockade Enhances T-cell Activity and Antitumor Efficacy of Imatinib in Gastrointestinal Stromal Tumors. Clin Cancer Res 2016; 23:454-465. [PMID: 27470968 DOI: 10.1158/1078-0432.ccr-16-1163] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2016] [Revised: 06/28/2016] [Accepted: 07/14/2016] [Indexed: 12/22/2022]
Abstract
PURPOSE Tyrosine kinase inhibitors are effective in gastrointestinal stromal tumors (GISTs) but often are of transient benefit as resistance commonly develops. Immunotherapy, particularly blockade of the inhibitory receptor programmed death 1 (PD-1) or the ligand programmed death ligand 1 (PD-L1), has shown effectiveness in a variety of cancers. The functional effects of PD-1/PD-L1 blockade are unknown in GISTs. EXPERIMENTAL DESIGN We analyzed tumor and matched blood samples from 85 patients with GISTs and determined the expression of immune checkpoint molecules using flow cytometry. We investigated the combination of imatinib with PD-1/PD-L1 blockade in KitV558Δ/+ mice that develop GISTs. RESULTS The inhibitory receptors PD-1, lymphocyte activation gene 3, and T-cell immunoglobulin mucin-3 were upregulated on tumor-infiltrating T cells compared with T cells from matched blood. PD-1 expression on T cells was highest in imatinib-treated human GISTs. Meanwhile, intratumoral PD-L1 expression was variable. In human GIST cell lines, treatment with imatinib abrogated the IFNγ-induced upregulation of PD-L1 via STAT1 inhibition. In KitV558Δ/+ mice, imatinib downregulated IFNγ-related genes and reduced PD-L1 expression on tumor cells. PD-1 and PD-L1 blockade in vivo each had no efficacy alone but enhanced the antitumor effects of imatinib by increasing T-cell effector function in the presence of KIT and IDO inhibition. CONCLUSIONS PD-1/PD-L1 blockade is a promising strategy to improve the effects of targeted therapy in GISTs. Collectively, our results provide the rationale to combine these agents in human GISTs. Clin Cancer Res; 23(2); 454-65. ©2016 AACR.
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Affiliation(s)
- Adrian M Seifert
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Shan Zeng
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jennifer Q Zhang
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Teresa S Kim
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Noah A Cohen
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Michael J Beckman
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Benjamin D Medina
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Joanna H Maltbaek
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jennifer K Loo
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Megan H Crawley
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ferdinand Rossi
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.,Department of Developmental Biology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Peter Besmer
- Department of Developmental Biology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Cristina R Antonescu
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ronald P DeMatteo
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
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41
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Saturday GA, Lasota J, Frost D, Brasky KB, Hubbard G, Miettinen M. KIT-positive Gastrointestinal Stromal Tumor in a 22-year-old Male Chimpanzee (Pan troglodites). Vet Pathol 2016; 42:362-5. [PMID: 15872385 DOI: 10.1354/vp.42-3-362] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Gastrointestinal stromal tumors (GIST), KIT-positive and KIT signaling driven or platelet-derived growth factor receptor α (PDGFRA) signaling driven mesenchymal tumors, are poorly known in nonhuman primates. Availability of KIT- and PDGFRA-inhibitor drug imatinib mesylate has greatly raised the interest for these tumors. At necropsy of a 22-year-old male chimpanzee, a round, firm 2-cm intramural tumor was incidentally found in the midbody of the stomach and diagnosed as a GIST. Histologically, the mass was composed of spindle to polygonal epithelioid cells arranged in short to intermediate-length, interlacing streams, bundles, and nodular whorls often separated by hyalinized eosinophilic matrix. The mitotic rate was a maximum 1/50 high-power field. Immunohistochemically, the tumor cells were diffusely positive for KIT and CD34, focally positive for α-smooth muscle actin, and negative for muscle specific actin, desmin, S-100 protein, synaptophy-sin, and glial fibrillary acidic protein. Because the majority of human GISTs have gain-of-function KIT or PDGFRA mutations, genomic sequences of KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18 from this chimpanzee GIST were polymerase chain reaction amplified and sequenced. However, no mutation was identified in the analyzed “mutational hot spots.” This study is the first extensive histomorphologic, immunohistochemical, and molecular genetic analysis of a chimpanzee GIST. More cases of nonhuman primate GISTs should be analyzed to discover the clinicopathologic spectrum of GISTs in these species.
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Affiliation(s)
- G A Saturday
- Department of Veterinary Pathology, Armed Forces Institute of Pathology, 14th and Alaska Avenue, Northwest, Building 54, Room G117, Washington, DC 20306-6000, USA.
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42
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Schroeder B, Li Z, Cranmer LD, Jones RL, Pollack SM. Targeting gastrointestinal stromal tumors: the role of regorafenib. Onco Targets Ther 2016; 9:3009-16. [PMID: 27284251 PMCID: PMC4881930 DOI: 10.2147/ott.s104081] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Gastrointestinal stromal tumor (GIST) is a devastating disease in the metastatic setting, but its natural history has been dramatically altered by the development of small molecule tyrosine kinase inhibitors, most notably imatinib. Although patients with advanced GIST live much longer today than they did in the past, imatinib-refractory disease remains a tremendous problem. For disease that is refractory to imatinib and sunitinib, regorafenib is an excellent option. In this review, we discuss the biology and clinical work establishing regorafenib as the standard of care for advanced GIST refractory to both imatinib and sunitinib.
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Affiliation(s)
- Brett Schroeder
- College of Human Medicine, Michigan State University, Grand Rapids, MI, USA
| | - Zula Li
- Division of Medical Oncology, University of Washington, Seattle, WA, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Lee D Cranmer
- Division of Medical Oncology, University of Washington, Seattle, WA, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Robin L Jones
- Royal Marsden Hospital, Institute of Cancer Research, London, UK
| | - Seth M Pollack
- Division of Medical Oncology, University of Washington, Seattle, WA, USA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
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43
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Wang Q, Liu F, Wang B, Zou F, Chen C, Liu X, Wang A, Qi S, Wang W, Qi Z, Zhao Z, Hu Z, Wang W, Wang L, Zhang S, Wang Y, Liu J, Liu Q. Discovery of N-(3-((1-Isonicotinoylpiperidin-4-yl)oxy)-4-methylphenyl)-3-(trifluoromethyl)benzamide (CHMFL-KIT-110) as a Selective, Potent, and Orally Available Type II c-KIT Kinase Inhibitor for Gastrointestinal Stromal Tumors (GISTs). J Med Chem 2016; 59:3964-79. [PMID: 27077705 DOI: 10.1021/acs.jmedchem.6b00200] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
c-KIT kinase is a validated drug discovery target for gastrointestinal stromal tumors (GISTs). Clinically used c-KIT kinase inhibitors, i.e., Imatinib and Sunitinib, bear other important targets such as ABL or FLT3 kinases. Here we report our discovery of a more selective c-KIT inhibitor, compound 13 (CHMFL-KIT-110), which completely abolished ABL and FLT3 kinase activity. KinomeScan selectivity profiling (468 kinases) of 13 exhibited a high selectivity (S score (1) = 0.01). 13 displayed great antiproliferative efficacy against GISTs cell lines GIST-T1 and GIST-882 (GI50: 0.021 and 0.043 μM, respectively). In the cellular context, it effectively affected c-KIT-mediated signaling pathways and induced apoptosis as well as cell cycle arrest. In addition, 13 possessed acceptable bioavailability (36%) and effectively suppressed the tumor growth in GIST-T1 cell inoculated xenograft model without apparent toxicity. 13 currently is undergoing extensive preclinical evaluation and might be a potential drug candidate for GISTs.
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Affiliation(s)
- Qiang Wang
- High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.,CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.,Center for Precision Medicine, CAS (Hefei) Institute of Technology Innovation, Hefei Institute of Physical Science, Chinese Academy of Sciences , Hefei, Anhui 230088, P. R. China
| | - Feiyang Liu
- High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.,University of Science and Technology of China , Hefei, Anhui 230036, P. R. China
| | - Beilei Wang
- High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.,CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.,Center for Precision Medicine, CAS (Hefei) Institute of Technology Innovation, Hefei Institute of Physical Science, Chinese Academy of Sciences , Hefei, Anhui 230088, P. R. China
| | - Fengming Zou
- High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.,CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.,Center for Precision Medicine, CAS (Hefei) Institute of Technology Innovation, Hefei Institute of Physical Science, Chinese Academy of Sciences , Hefei, Anhui 230088, P. R. China
| | - Cheng Chen
- High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.,CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.,Center for Precision Medicine, CAS (Hefei) Institute of Technology Innovation, Hefei Institute of Physical Science, Chinese Academy of Sciences , Hefei, Anhui 230088, P. R. China
| | - Xiaochuan Liu
- High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.,Department of Chemistry, University of Science and Technology of China , Hefei, Anhui 230036, P. R. China
| | - Aoli Wang
- High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.,University of Science and Technology of China , Hefei, Anhui 230036, P. R. China
| | - Shuang Qi
- High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.,CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.,Center for Precision Medicine, CAS (Hefei) Institute of Technology Innovation, Hefei Institute of Physical Science, Chinese Academy of Sciences , Hefei, Anhui 230088, P. R. China
| | - Wenchao Wang
- High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.,CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.,Center for Precision Medicine, CAS (Hefei) Institute of Technology Innovation, Hefei Institute of Physical Science, Chinese Academy of Sciences , Hefei, Anhui 230088, P. R. China
| | - Ziping Qi
- High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.,CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.,Center for Precision Medicine, CAS (Hefei) Institute of Technology Innovation, Hefei Institute of Physical Science, Chinese Academy of Sciences , Hefei, Anhui 230088, P. R. China
| | - Zheng Zhao
- High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.,CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.,Center for Precision Medicine, CAS (Hefei) Institute of Technology Innovation, Hefei Institute of Physical Science, Chinese Academy of Sciences , Hefei, Anhui 230088, P. R. China
| | - Zhenquan Hu
- High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.,CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.,Center for Precision Medicine, CAS (Hefei) Institute of Technology Innovation, Hefei Institute of Physical Science, Chinese Academy of Sciences , Hefei, Anhui 230088, P. R. China
| | - Wei Wang
- High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.,CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.,Center for Precision Medicine, CAS (Hefei) Institute of Technology Innovation, Hefei Institute of Physical Science, Chinese Academy of Sciences , Hefei, Anhui 230088, P. R. China
| | - Li Wang
- High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.,CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.,Center for Precision Medicine, CAS (Hefei) Institute of Technology Innovation, Hefei Institute of Physical Science, Chinese Academy of Sciences , Hefei, Anhui 230088, P. R. China
| | - Shanchun Zhang
- CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.,Hefei Cosource Medicine Technology Co., LTD , 358 Ganquan Road, Hefei, Anhui 230031, P. R. China
| | - Yuexiang Wang
- SIBS (Institute of Health Sciences)-Changzheng Hospital Joint Center for Translational Medicine, Institute of Health Sciences, Shanghai Changzheng Hospital, Institutes for Translational Medicine (CAS-SMMU) , Shanghai 200031, China.,Key Laboratory of Stem Cell Biology, Institute of Health Sciences, SIBS, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine , Shanghai 200031, China.,Collaborative Innovation Center of Systems Biomedicine , Shanghai 200025, China
| | - Jing Liu
- High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.,CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.,Center for Precision Medicine, CAS (Hefei) Institute of Technology Innovation, Hefei Institute of Physical Science, Chinese Academy of Sciences , Hefei, Anhui 230088, P. R. China
| | - Qingsong Liu
- High Magnetic Field Laboratory, Chinese Academy of Sciences , Mailbox 1110, 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.,CHMFL-HCMTC Target Therapy Joint Laboratory , 350 Shushanhu Road, Hefei, Anhui 230031, P. R. China.,Center for Precision Medicine, CAS (Hefei) Institute of Technology Innovation, Hefei Institute of Physical Science, Chinese Academy of Sciences , Hefei, Anhui 230088, P. R. China.,University of Science and Technology of China , Hefei, Anhui 230036, P. R. China
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Abstract
Immunotherapy is now evolving into a major therapeutic option for cancer patients. Such clinical advances also promote massive interest in the search for novel immunotherapy targets, and to understand the mechanism of action of current drugs. It is projected that a series of novel immunotherapy agents will be developed and assessed for their therapeutic activity. In light of this, in vivo experimental mouse models that recapitulate human malignancies serve as valuable tools to validate the efficacy and safety profile of immunotherapy agents, before their transition into clinical trials. In this review, we will discuss the major classes of experimental mouse models of cancer commonly used for immunotherapy assessment and provide examples to guide the selection of appropriate models. We present some new data concerning the utility of a carcinogen-induced tumor model for comparing immunotherapies and combining immunotherapy with chemotherapy. We will also highlight some recent advances in experimental modeling of human malignancies in mice that are leading towards personalized therapy in patients.
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Affiliation(s)
- Shin Foong Ngiow
- QIMR Berghofer Medical Research Institute, Herston, QLD, Australia; University of Queensland, Herston, QLD, Australia
| | - Sherene Loi
- Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; University of Melbourne, Parkville, VIC, Australia
| | - David Thomas
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | - Mark J Smyth
- QIMR Berghofer Medical Research Institute, Herston, QLD, Australia; University of Queensland, Herston, QLD, Australia; Peter MacCallum Cancer Centre, East Melbourne, VIC, Australia; University of Melbourne, Parkville, VIC, Australia.
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45
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Analysis of c-KIT exon 11 mutations in canine gastrointestinal stromal tumours. Vet J 2016; 207:118-123. [DOI: 10.1016/j.tvjl.2015.10.051] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Revised: 09/18/2015] [Accepted: 10/24/2015] [Indexed: 12/27/2022]
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46
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Kajimoto N, Nakai N, Ohkouchi M, Hashikura Y, Liu-Kimura NN, Isozaki K, Hirota S. Characterization of various types of mast cells derived from model mice of familial gastrointestinal stromal tumors with KIT-Asp818Tyr mutation. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:11970-11982. [PMID: 26722383 PMCID: PMC4680328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Accepted: 09/28/2015] [Indexed: 06/05/2023]
Abstract
Sporadic mast cell neoplasms and gastrointestinal stromal tumors (GISTs) often have various types of somatic gain-of-function mutations of the c-kit gene which encodes a receptor tyrosine kinase, KIT. Several types of germline gain-of-function mutations of the c-kit gene have been detected in families with multiple GISTs. All three types of model mice for the familial GISTs with germline c-kit gene mutations at exon 11, 13 or 17 show development of GIST, while they are different from each other in skin mast cell number. Skin mast cell number in the model mice with exon 17 mutation was unchanged compared to the corresponding wild-type mice. In the present study, we characterized various types of mast cells derived from the model mice with exon 17 mutation (KIT-Asp818Tyr) corresponding to human familial GIST case with human KIT-Asp820Tyr to clarify the role of the c-kit gene mutation in mast cells. Bone marrow-derived cultured mast cells (BMMCs) derived from wild-type mice, heterozygotes and homozygotes were used for the experiments. Immortalized BMMCs, designated as IMC-G4 cells, derived from BMMCs of a homozygote during long-term culture were also used. Ultrastructure, histamine contents, proliferation profiles and phosphorylation of various signaling molecules in those cells were examined. In IMC-G4 cells, presence of additional mutation(s) of the c-kit gene and effect of KIT inhibitors on both KIT autophosphorylation and cell proliferation were also analyzed. We demonstrated that KIT-Asp818Tyr did not affect ultrastructure and proliferation profiles but did histamine contents in BMMCs. IMC-G4 cells had an additional novel c-kit gene mutation of KIT-Tyr421Cys which is considered to induce neoplastic transformation of mouse mast cells and the mutation appeared to be resistant to a KIT inhibitor of imatinib but sensitive to another KIT inhibitor of nilotinib. IMC-G4 cells might be a useful mast cell line to investigate mast cell biology.
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Affiliation(s)
- Noriko Kajimoto
- Department of Surgical Pathology, Hyogo College of Medicine Hyogo, Japan
| | - Norihiro Nakai
- Department of Surgical Pathology, Hyogo College of Medicine Hyogo, Japan
| | - Mizuka Ohkouchi
- Department of Surgical Pathology, Hyogo College of Medicine Hyogo, Japan
| | - Yuka Hashikura
- Department of Surgical Pathology, Hyogo College of Medicine Hyogo, Japan
| | | | - Koji Isozaki
- Department of Surgical Pathology, Hyogo College of Medicine Hyogo, Japan
| | - Seiichi Hirota
- Department of Surgical Pathology, Hyogo College of Medicine Hyogo, Japan
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47
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Coffelt SB, de Visser KE. Immune-mediated mechanisms influencing the efficacy of anticancer therapies. Trends Immunol 2015; 36:198-216. [PMID: 25857662 DOI: 10.1016/j.it.2015.02.006] [Citation(s) in RCA: 106] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 02/18/2015] [Accepted: 02/18/2015] [Indexed: 01/26/2023]
Abstract
Conventional anticancer therapies, such as chemotherapy, radiotherapy, and targeted therapy, are designed to kill cancer cells. However, the efficacy of anticancer therapies is not only determined by their direct effects on cancer cells but also by off-target effects within the host immune system. Cytotoxic treatment regimens elicit several changes in immune-related parameters including the composition, phenotype, and function of immune cells. Here we discuss the impact of innate and adaptive immune cells on the success of anticancer therapy. In this context we examine the opportunities to exploit host immune responses to boost tumor clearing, and highlight the challenges facing the treatment of advanced metastatic disease.
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Affiliation(s)
- Seth B Coffelt
- Division of Immunology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
| | - Karin E de Visser
- Division of Immunology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.
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48
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Abstract
Approximately 85-90% of adult gastrointestinal stromal tumors (GISTs) harbor KIT and PDGFRA mutations. The remaining cases, including the majority of pediatric GISTs, lack these mutations, and have been designated as KIT/PDGFRA wild-type (WT) GISTs. Nearly 15% of WT GISTs harbor BRAF mutations, while others arise in patients with type I neurofibromatosis. Recent work has confirmed that 20-40% of KIT/PDGFRA WT GISTs show loss of function of succinate dehydrogenase complex. Less than 5% of GISTs lack known molecular alterations ("quadruple-negative" GISTs). Thus, it is important to consider genotyping these tumors to help better define their clinical behavior and therapy.
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Affiliation(s)
- Deepa T Patil
- Department of Pathology, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, 9500 Euclid Avenue, L-25, Cleveland, OH 44195, USA.
| | - Brian P Rubin
- Department of Pathology, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, 9500 Euclid Avenue, L-25, Cleveland, OH 44195, USA; Department of Molecular Genetics, Cleveland Clinic and Lerner Research Institute, 9500 Euclid Avenue, L-25, Cleveland, OH 44195, USA
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49
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Abstract
A confluence of factors, most prominently the recognition of GI stromal tumor (GIST) as a specific sarcoma subtype and the availability of imatinib, led to the “Big Bang” of GIST therapy (ie, the successful treatment of the first patient with GIST with imatinib in 2000). The trail blazed by imatinib for chronic myelogenous leukemia and GIST has become a desired route to regulatory approval of an increasing number of oral kinase inhibitors and other novel therapeutics. In this review, the status of GIST management before and after GIST's “Big Bang” and new steps being taken to further improve on therapy are reviewed.
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Affiliation(s)
- Angela Cioffi
- All authors: Tisch Cancer Institute, Mount Sinai Medical Center, New York, NY
| | - Robert G. Maki
- All authors: Tisch Cancer Institute, Mount Sinai Medical Center, New York, NY
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50
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Cohen NA, Zeng S, Seifert AM, Kim TS, Sorenson EC, Greer JB, Beckman MJ, Santamaria-Barria JA, Crawley MH, Green BL, Rossi F, Besmer P, Antonescu CR, DeMatteo RP. Pharmacological Inhibition of KIT Activates MET Signaling in Gastrointestinal Stromal Tumors. Cancer Res 2015; 75:2061-70. [PMID: 25836719 DOI: 10.1158/0008-5472.can-14-2564] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2014] [Accepted: 02/19/2015] [Indexed: 02/07/2023]
Abstract
Gastrointestinal stromal tumors (GIST) are the most common adult sarcomas and the oncogenic driver is usually a KIT or PDGFRA mutation. Although GISTs are often initially sensitive to imatinib or other tyrosine kinase inhibitors, resistance generally develops, necessitating backup strategies for therapy. In this study, we determined that a subset of human GIST specimens that acquired imatinib resistance acquired expression of activated forms of the MET oncogene. MET activation also developed after imatinib therapy in a mouse model of GIST (KitV558del/+ mice), where it was associated with increased tumor hypoxia. MET activation also occurred in imatinib-sensitive human GIST cell lines after imatinib treatment in vitro. MET inhibition by crizotinib or RNA interference was cytotoxic to an imatinib-resistant human GIST cell population. Moreover, combining crizotinib and imatinib was more effective than imatinib alone in imatinib-sensitive GIST models. Finally, cabozantinib, a dual MET and KIT small-molecule inhibitor, was markedly more effective than imatinib in multiple preclinical models of imatinib-sensitive and imatinib-resistant GIST. Collectively, our findings showed that activation of compensatory MET signaling by KIT inhibition may contribute to tumor resistance. Furthermore, our work offered a preclinical proof of concept for MET inhibition by cabozantinib as an effective strategy for GIST treatment.
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Affiliation(s)
- Noah A Cohen
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Shan Zeng
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Adrian M Seifert
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Teresa S Kim
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Eric C Sorenson
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jonathan B Greer
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Michael J Beckman
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | | | - Megan H Crawley
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Benjamin L Green
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ferdinand Rossi
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Peter Besmer
- Department of Developmental Biology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Cristina R Antonescu
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Ronald P DeMatteo
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
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