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Wang Y, Zhang H, La Ferlita A, Sp N, Goryunova M, Sarchet P, Hu Z, Sorkin M, Kim A, Huang H, Zhu H, Tsung A, Pollock RE, Beane JD. Phosphorylation of IWS1 by AKT maintains liposarcoma tumor heterogeneity through preservation of cancer stem cell phenotypes and mesenchymal-epithelial plasticity. Oncogenesis 2023; 12:30. [PMID: 37237004 DOI: 10.1038/s41389-023-00469-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 04/07/2023] [Accepted: 04/17/2023] [Indexed: 05/28/2023] Open
Abstract
Chemotherapy remains the mainstay of treatment for patients with advanced liposarcoma (LPS), but response rates are only 25% and the overall survival at 5 years is dismal at 20-34%. Translation of other therapies have not been successful and there has been no significant improvement in prognosis for nearly 20 years. The aberrant activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway has been implicated in the aggressive clinical behavior LPS and in resistance to chemotherapy, but the precise mechanism remains elusive and efforts to target AKT clinically have failed. Here we show that the AKT-mediated phosphorylation of the transcription elongation factor IWS1, promotes the maintenance of cancer stem cells in both cell and xenograft models of LPS. In addition, phosphorylation of IWS1 by AKT contributes to a "metastable" cell phenotype, characterized by mesenchymal/epithelial plasticity. The expression of phosphorylated IWS1 also promotes anchorage-dependent and independent growth, cell migration, invasion, and tumor metastasis. In patients with LPS, IWS1 expression is associated with reduced overall survival, increased frequency of recurrence, and shorter time to relapse after resection. These findings indicate that IWS1-mediated transcription elongation is an important regulator of human LPS pathobiology in an AKT-dependent manner and implicate IWS1 as an important molecular target to treat LPS.
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Affiliation(s)
- Yu Wang
- Department of Surgery, Division of Surgical Oncology, James Cancer Center, The Ohio State University, Columbus, OH, USA
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Hongji Zhang
- Department of Surgery, Division of Surgical Oncology, James Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Alessandro La Ferlita
- Department of Cancer Biology and Genetics, James Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Nipin Sp
- Department of Surgery, Division of Surgical Oncology, James Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Marina Goryunova
- Department of Surgery, Division of Surgical Oncology, James Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Patricia Sarchet
- Department of Surgery, Division of Surgical Oncology, James Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Zhiwei Hu
- Department of Surgery, Division of Surgical Oncology, James Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Michael Sorkin
- Department of Plastic and Reconstructive Surgery, James Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Alex Kim
- Department of Surgery, Division of Surgical Oncology, James Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Hai Huang
- Department of Surgery, Division of Surgical Oncology, James Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Hua Zhu
- Department of Surgery, Division of Cardiac Surgery, Wexner Medical Center, The Ohio State University, Columbus, OH, USA
| | - Allan Tsung
- Department of Surgery, Division of Surgical Oncology, James Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Raphael E Pollock
- Department of Surgery, Division of Surgical Oncology, James Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Joal D Beane
- Department of Surgery, Division of Surgical Oncology, James Cancer Center, The Ohio State University, Columbus, OH, USA.
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Syamprasad NP, Madje N, Bachannagari J, Jannu AK, Jain S, Tene K, Shantanu PA, Naidu V, Chella N. Niclosamide nanocrystal for enhanced in-vivo efficacy against gastrointestinal stromal tumor via regulating EGFR/STAT-3/DR-4 axis. J Drug Deliv Sci Technol 2023. [DOI: 10.1016/j.jddst.2023.104221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
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Guo J, Feng S, Yu H, Ou B, Jiang D, Zhuang W, Ding C, Chen X, Zhang M, Ling Y, Zeng Y, Qiu H. Transcriptomic study of gastrointestinal stromal tumors with liver metastasis. Front Genet 2023; 14:1007135. [PMID: 36911388 PMCID: PMC9996342 DOI: 10.3389/fgene.2023.1007135] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Accepted: 02/10/2023] [Indexed: 02/25/2023] Open
Abstract
Introduction: GIST (gastrointestinal stromal tumor) is the most prominent mesenchymal neoplasms of the gastrointestinal tract, and liver is the most common metastasis site for GIST. The molecular mechanism leading to liver metastasis of GIST is currently unclear. Methods: With the goal of revealing the underlying mechanism, we performed whole-genome gene expression profiling on 18 pairs of RNA samples comprised of GIST tissues (with liver metastasis) and corresponding non-tumor tissues. After identifying differentially expressed gene, functional annotation and signal pathway analyses were conducted. GSE13861, datasets that compare GIST (without liver metastasis) with adjacent tissues, served as a comparison. Results: A total of 492 up-regulated genes and 629 down-regulated genes were identified as differentially expressed genes between liver metastasis tissues and non-tumor tissues. We characterized expression patterns of DEGs identified from our cohort and GSE13861 that show signatures of enrichment for functionality. In subsequent gene set enrichment analysis, differentially expressed genes were mainly enriched in Epithelial Mesenchymal Transition in both datasets. 493 genes were overlapped among our whole-genome gene expression profiling results and GSE13861, consisting 188 up-regulated genes and 305 down-regulated genes. By using CytoHubba plugin of Cytoscape, CDH1, CD34, KIT, PROM1, SOX9, FGF2, CD24, ALDH1A1, JAG1 and NES were identified as top ten hub genes in tumorigenesis and liver metastasis of GIST. higher expression levels of FGF2, JAG1, CD34, ALDH1A1 and the lower expression level of CDH1 were respectively associated with unfavorable overall survival. Meanwhile higher expression levels of CD34, FGF2, KIT, JAG1, ALDH1A were correlated with worse disease-free survival. Discussion: The present study may help to provide candidate pathways and targets for treatment of GIST and prevention methods to liver metastasis.
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Affiliation(s)
- Jianrong Guo
- Department of Gastric Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Shoucheng Feng
- Department of Gastric Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Hong Yu
- Department of Gastric Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Biyi Ou
- Department of Gastric Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Dan Jiang
- Department of Gastric Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Wei Zhuang
- Department of Pharmacy, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, Fujian, China
| | - Chao Ding
- Department of Gastric Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Xiaojiang Chen
- Department of Gastric Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Miaoquan Zhang
- Department of Gastric Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yudong Ling
- Department of Gastric Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Yi Zeng
- Department of Gastric Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Haibo Qiu
- Department of Gastric Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China
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Bahrami A, Ferns GA. Diagnostic, Prognostic, and Therapeutic Value of miR-148b in Human Cancers. Curr Mol Med 2022; 22:860-869. [PMID: 34961461 DOI: 10.2174/1566524021666211213123315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 07/06/2021] [Accepted: 11/05/2021] [Indexed: 11/22/2022]
Abstract
MicroRNAs (miRs) is a class of conserved, small, noncoding RNA molecules that modulate gene expression post-transcriptionally. miR-148b is a member of miR- 148/152 family generally known to be a tumor suppressor via its effect on different signaling pathways and regulatory genes. Aberrant expression of miR-148b has recently been shown to be responsible for tumorigenesis of several different cancer types. This review discusses the current evidence regarding the involvement of miR-148b expression in human cancers and its potential clinical importance for tumor diagnosis, prognosis, and therapeutics.
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Affiliation(s)
- Afsane Bahrami
- Clinical Research Development Unit, Imam Reza Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Division of Medical Education, Brighton & Sussex Medical School, Brighton, Sussex, UK
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Molecular-Genetic Basis of Gastrointestinal Stromal Tumor Personalized Therapy by Receptor Tyrosine Kinase Inhibitors (A Review). Pharm Chem J 2021. [DOI: 10.1007/s11094-021-02419-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Yoon C, Lu J, Yi BC, Chang KK, Simon MC, Ryeom S, Yoon SS. PI3K/Akt pathway and Nanog maintain cancer stem cells in sarcomas. Oncogenesis 2021; 10:12. [PMID: 33468992 PMCID: PMC7815726 DOI: 10.1038/s41389-020-00300-z] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Revised: 12/07/2020] [Accepted: 12/10/2020] [Indexed: 12/21/2022] Open
Abstract
The self-renewal transcription factor Nanog and the phosphoinositide 3-kinase (PI3K)-Akt pathway are known to be essential for maintenance of mesenchymal stem cells. We evaluated their contribution to the maintenance of CD133(+) cancer stem-like cells (CSCs) and spheroid-forming cells in patient-derived cell lines from three human sarcoma subtypes: HT1080 fibrosarcoma, SK-LMS-1 leiomyosarcoma, and DDLS8817 dedifferentiated liposarcoma. Levels of Nanog and activated Akt were significantly higher in sarcoma cells grown as spheroids or sorted for CD133 expression to enrich for CSCs. shRNA knockdown of Nanog decreased spheroid formation 10- to 14-fold, and reversed resistance to both doxorubicin and radiation in vitro and in H1080 flank xenografts. In the HT1080 xenograft model, doxorubicin and Nanog knockdown reduced tumor growth by 34% and 45%, respectively, and the combination reduced tumor growth by 74%. Using a human phospho-kinase antibody array, Akt1/2 signaling, known to regulate Nanog, was found to be highly activated in sarcoma spheroid cells compared with monolayer cells. Pharmacologic inhibition of Akt using LY294002 and Akt1/2 knockdown using shRNA in sarcoma CSCs decreased Nanog expression and spheroid formation and reversed chemotherapy resistance. Akt1/2 inhibition combined with doxorubicin treatment of HT1080 flank xenografts reduced tumor growth by 73%. Finally, in a human sarcoma tumor microarray, expression of CD133, Nanog, and phospho-Akt were 1.8- to 6.8-fold higher in tumor tissue compared with normal tissue. Together, these results indicate that the Akt1/2-Nanog pathway is critical for maintenance of sarcoma CSCs and spheroid-forming cells, supporting further exploration of this pathway as a therapeutic target in sarcoma.
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Affiliation(s)
- Changhwan Yoon
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jun Lu
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Gastric Surgery, Fujian Medical University Union Hospital, Fujian, China
| | - Brendan C Yi
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kevin K Chang
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - M Celeste Simon
- Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Sandra Ryeom
- Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Sam S Yoon
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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Boichuk S, Bikinieva F, Nurgatina I, Dunaev P, Valeeva E, Aukhadieva A, Sabirov A, Galembikova A. Inhibition of AKT-Signaling Sensitizes Soft Tissue Sarcomas (STS) and Gastrointestinal Stromal Tumors (GIST) to Doxorubicin via Targeting of Homology-Mediated DNA Repair. Int J Mol Sci 2020; 21:E8842. [PMID: 33266502 PMCID: PMC7700672 DOI: 10.3390/ijms21228842] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Revised: 11/16/2020] [Accepted: 11/20/2020] [Indexed: 12/23/2022] Open
Abstract
Activation of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway is well documented for a broad spectrum of human malignancies supporting their growth and progression. Accumulating evidence has also implicated AKT as a potent modulator of anti-cancer therapies via regulation of DNA damage response and repair (DDR) induced by certain chemotherapeutic agents and ionizing radiation (IR). In the present study, we examined the role of AKT signaling in regulating of Rad51 turnover and cytotoxic effects of topoisomerase II inhibitor, doxorubicin (Dox) in soft tissue sarcomas (STS) and gastrointestinal stromal tumors (GIST) in vitro. Blocking of AKT signaling (MK-2206) enhanced cytotoxic and pro-apoptotic effects of Dox in vast majority of STS and GIST cell lines. The phosphorylated form of Akt co-immunoprecipitates with Rad51 after Dox-induced DNA damage, whereas Akt inhibition interrupts this interaction and decreases Rad51 protein level by enhancing protein instability via proteasome-dependent degradation. Inhibition of Akt signaling in Dox-treated cells was associated with the increased number of γ-H2AX-positive cells, decrease of Rad51 foci formation and its colocalization with γ-H2AX foci, thereby revealing unsuccessful DDR events. This was also in consistency with an increase of tail moment (TM) and olive tail moment (OTM) in Dox-treated GIST and STS cells cultured in presence of Akt inhibitor after Dox washout. Altogether, our data illustrates that inhibition of AKT signaling is STS and GIST might potentiate the cytotoxic effect of topoisomerase II inhibitors via attenuating the homology-mediated DNA repair.
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Affiliation(s)
- Sergei Boichuk
- Department of Pathology, Kazan State Medical University, 420012 Kazan, Russia; (F.B.); (I.N.); (P.D.); (A.A.); (A.G.)
- Central Research Laboratory, Kazan State Medical University, 420012 Kazan, Russia;
| | - Firuza Bikinieva
- Department of Pathology, Kazan State Medical University, 420012 Kazan, Russia; (F.B.); (I.N.); (P.D.); (A.A.); (A.G.)
| | - Ilmira Nurgatina
- Department of Pathology, Kazan State Medical University, 420012 Kazan, Russia; (F.B.); (I.N.); (P.D.); (A.A.); (A.G.)
| | - Pavel Dunaev
- Department of Pathology, Kazan State Medical University, 420012 Kazan, Russia; (F.B.); (I.N.); (P.D.); (A.A.); (A.G.)
| | - Elena Valeeva
- Central Research Laboratory, Kazan State Medical University, 420012 Kazan, Russia;
| | - Aida Aukhadieva
- Department of Pathology, Kazan State Medical University, 420012 Kazan, Russia; (F.B.); (I.N.); (P.D.); (A.A.); (A.G.)
| | - Alexey Sabirov
- Department of Pathology, Tatarstan Cancer Center, 420029 Kazan, Russia;
| | - Aigul Galembikova
- Department of Pathology, Kazan State Medical University, 420012 Kazan, Russia; (F.B.); (I.N.); (P.D.); (A.A.); (A.G.)
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8
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Duan Y, Haybaeck J, Yang Z. Therapeutic Potential of PI3K/AKT/mTOR Pathway in Gastrointestinal Stromal Tumors: Rationale and Progress. Cancers (Basel) 2020; 12:2972. [PMID: 33066449 PMCID: PMC7602170 DOI: 10.3390/cancers12102972] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 10/03/2020] [Accepted: 10/12/2020] [Indexed: 12/12/2022] Open
Abstract
Gastrointestinal stromal tumor (GIST) originates from interstitial cells of Cajal (ICCs) in the myenteric plexus of the gastrointestinal tract. Most GISTs arise due to mutations of KIT and PDGFRA gene activation, encoding the receptor tyrosine kinase (RTK). The clinical use of the RTK inhibitor imatinib has significantly improved the management of GIST patients; however, imatinib resistance remains a challenge. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is a critical survival pathway for cell proliferation, apoptosis, autophagy and translation in neoplasms. Constitutive autophosphorylation of RTKs has an impact on the activation of the PI3K/AKT/mTOR pathway. In several preclinical and early-stage clinical trials PI3K/AKT/mTOR signaling inhibition has been considered as a promising targeted therapy strategy for GISTs. Various inhibitory drugs targeting different parts of the PI3K/AKT/mTOR pathway are currently being investigated in phase I and phase II clinical trials. This review highlights the progress for PI3K/AKT/mTOR-dependent mechanisms in GISTs, and explores the relationship between mTOR downstream signals, in particular, eukaryotic initiation factors (eIFs) and the development of GISTs, which may be instrumental for identifying novel therapeutic targets.
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Affiliation(s)
- Yi Duan
- Department of Pathology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China;
| | - Johannes Haybaeck
- Department of Pathology, Neuropathology and Molecular Pathology, Medical University of Innsbruck, 6020 Innsbruck, Austria
- Diagnostic & Research Center for Molecular BioMedicine, Institute of Pathology, Medical University of Graz, 8010 Graz, Austria
| | - Zhihui Yang
- Department of Pathology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China;
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Gokozan HN, Bomeisl P. Succinate dehydrogenase-deficient gastrointestinal stromal tumor of stomach diagnosed by endoscopic ultrasound-guided fine-needle biopsy: Report of a distinct subtype in cytology. Diagn Cytopathol 2020; 48:1328-1332. [PMID: 32870601 DOI: 10.1002/dc.24591] [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] [Received: 05/08/2020] [Revised: 07/06/2020] [Accepted: 08/03/2020] [Indexed: 02/04/2023]
Abstract
Succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (GISTs) are characterized by the lack of mutations in KIT receptor tyrosine kinase complex and platelet derived growth factor receptor-alpha (PDGFRA) that are commonly found in the majority of GISTs. SDH-deficient GISTs comprise approximately 5%-10% of all GISTs. This subset may be associated with Carney Triad and Carney-Stratakis syndrome. SDH-deficient GISTs show unique demographic, radiologic, morphologic findings, clinical behavior, and treatment response. To our knowledge, the identification and characterization of this subset of GISTs have not yet been described in the cytopathology literature. By understanding the clinical as well as the other unique features of this tumor, in addition to the rapidly evolving identification of specific molecular alterations and targeted therapies, cytopathologists may play an important role in the diagnosis and work-up of these patients to allow clinicians to better manage and treat them. We present a young female with gastric SDH-deficient GIST diagnosed by fine-needle biopsy with supporting surgical pathology follow-up and molecular confirmation. This report suggests that the diagnosis of SDH-deficient GIST can be made on cytology in the appropriate clinical setting by using cytomorphologic features and demonstrating SDH loss by IHC on the cell block. In addition, molecular testing may be possible on the cytology cell block or supernatant to confirm the diagnosis.
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Affiliation(s)
- Hamza Numan Gokozan
- Department of Pathology, University Hospitals Cleveland Medical Center/ Case Western Reserve University, Cleveland, Ohio, USA
| | - Philip Bomeisl
- Department of Pathology, University Hospitals Cleveland Medical Center/ Case Western Reserve University, Cleveland, Ohio, USA
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Hemming ML, Heinrich MC, Bauer S, George S. Translational insights into gastrointestinal stromal tumor and current clinical advances. Ann Oncol 2019; 29:2037-2045. [PMID: 30101284 DOI: 10.1093/annonc/mdy309] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Gastrointestinal stromal tumor (GIST) is the most common soft tissue sarcoma of the gastrointestinal tract and, in the vast majority of cases, is characterized by activating mutations in KIT or, less commonly, PDGFRA. Mutations in these type III receptor tyrosine kinases (RTKs) account for over 85% of GIST cases, and the majority of KIT primary mutations respond to treatment with the tyrosine kinase inhibitor (TKI) imatinib. However, drug resistance develops over time, most commonly due to secondary kinase mutations. Sunitinib and regorafenib are approved for the treatment of imatinib-resistant GIST in the second and third lines, respectively. However, resistance to these agents also develops and new therapeutic options are needed. In addition, a small number of GISTs harbor primary activating mutations that are resistant to currently available TKIs, highlighting an additional unmet medical need. Several novel and selective TKIs that overcome known mechanisms of resistance in GIST have been developed and show promise in early clinical trials. Additional emerging targeted therapies in GIST include modulation of cellular signaling pathways downstream of KIT, antibodies targeting KIT and PDGFRA and immune checkpoint inhibitors. These advancements highlight the rapid evolution in the understanding of this malignancy and provide perspective on the encouraging horizon of current and forthcoming therapeutic strategies for GIST.
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Affiliation(s)
- M L Hemming
- Department of Medical Oncology, Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA
| | - M C Heinrich
- VA Health Care System and Knight Cancer Institute, Oregon Health and Science University, Oregon, USA
| | - S Bauer
- Sarcoma Center, Western German Cancer Center and German Cancer Consortium (DKTK), Essen, Germany
| | - S George
- Department of Medical Oncology, Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, USA.
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Prognostic Role of miR-221 and miR-222 Expression in Cancer Patients: A Systematic Review and Meta-Analysis. Cancers (Basel) 2019; 11:cancers11070970. [PMID: 31336701 PMCID: PMC6678869 DOI: 10.3390/cancers11070970] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 07/08/2019] [Indexed: 12/13/2022] Open
Abstract
Background: A wealth of evidence has shown that microRNAs (miRNAs) can modulate specific genes, increasing our knowledge on the fine-tuning regulation of protein expression. miR-221 and miR-222 have been frequently identified as deregulated across different cancer types; however, their prognostic significance in cancer remains controversial. In view of these considerations, we performed an updated systematic review and meta-analysis of published data investigating the effects of miR-221/222 on overall survival (OS) and other secondary outcomes among cancer patients. A systematic search of PubMed, Web of Knowledge, and Cochrane Library databases was performed. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were used to assess the strength of association. Results: Fifty studies, analyzing 6086 patients, were included in the systematic review. Twenty-five studies for miR-221 and 17 studies for miR-222 which assessed OS were included in the meta-analysis. High expression of miR-221 and miR-222 significantly predicted poor OS (HR: 1.48, 95% CI: 1.14–1.93, p = 0.003 and HR: 1.90, 95% CI: 1.43–2.54, p < 0.001, respectively). Subgroup analysis revealed that the finding on miR-221 was not as robust as the one on miR-222. Furthermore, high miR-222 expression was also associated with worse progression-free survival and disease-free survival pooled with recurrence-free survival. Conclusions: The meta-analysis demonstrated that high expression of miR-222 is associated with poor prognosis in cancer patients, whereas the significance of miR-221 remains unclear. More work is required to fully elucidate the role of miR-221 and miR-222 in cancer prognosis, particularly in view of the limitations of existing results, including the significant heterogeneity and limited number of studies for some cancers.
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12
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Ravegnini G, Sammarini G, Moran S, Calice G, Indio V, Urbini M, Astolfi A, Zanotti F, Pantaleo MA, Hrelia P, Angelini S. Mechanisms of resistance to a PI3K inhibitor in gastrointestinal stromal tumors: an omic approach to identify novel druggable targets. Cancer Manag Res 2019; 11:6229-6244. [PMID: 31308757 PMCID: PMC6615718 DOI: 10.2147/cmar.s189661] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2018] [Accepted: 04/16/2019] [Indexed: 12/22/2022] Open
Abstract
Background: Gastrointestinal stromal tumors (GISTs) represent a worldwide paradigm of target therapy. The introduction of tyrosine kinase inhibitors has deeply changed the prognosis of GIST patients, however, the majority of them acquire secondary mutations and progress. Unfortunately, besides tyrosine-kinase inhibitors, no other therapeutic options are available. Therefore, it is mandatory to identify novel molecules and/or strategies to overcome the inevitable resistance. In this context, after promising preclinical data on the novel PI3K inhibitor BYL719, the NCT01735968 trial in GIST patients who had previously failed treatment with imatinib and sunitinib started. BYL719 has attracted our attention, and we comprehensively characterized genomic and transcriptomic changes taking place during resistance. Methods: For this purpose, we generated two in vitro GIST models of acquired resistance to BYL719 and performed an omic-based analysis by integrating RNA-sequencing, miRNA, and methylation profiles in sensitive and resistant cells. Results: We identified novel epigenomic mechanisms of pharmacological resistance in GISTs suggesting the existence of pathways involved in drug resistance and alternatively acquired mutations. Therefore, epigenomics should be taken into account as an alternative adaptive mechanism. Conclusion: Despite the fact that currently we do not have patients in treatment with BYL719 to verify this hypothesis, the most intriguing result is the involvement of H19 and PSTA1 in GIST resistance, which might represent druggable targets.
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Affiliation(s)
- Gloria Ravegnini
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Giulia Sammarini
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Sebastian Moran
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institue (Idibell), l'Hospitalet de Llobregat, Barcelona, Spain
| | - Giovanni Calice
- Laboratory of Preclinical and Translational Research, IRCCS-CROB, Referral Cancer Center of Basilicata, Rionero in Vulture, Italy
| | - Valentina Indio
- Giorgio Prodi Cancer Research Center, University of Bologna, Bologna, Italy
| | - Milena Urbini
- Giorgio Prodi Cancer Research Center, University of Bologna, Bologna, Italy
| | - Annalisa Astolfi
- Giorgio Prodi Cancer Research Center, University of Bologna, Bologna, Italy
| | - Federica Zanotti
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Maria A Pantaleo
- Giorgio Prodi Cancer Research Center, University of Bologna, Bologna, Italy.,Department of Specialized, Experimental, and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Patrizia Hrelia
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Sabrina Angelini
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
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Ravegnini G, Ricci R. Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumors: Small Steps Toward Personalized Medicine? Epigenet Insights 2019; 12:2516865719842534. [PMID: 31020269 PMCID: PMC6463228 DOI: 10.1177/2516865719842534] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Accepted: 03/08/2019] [Indexed: 12/12/2022] Open
Abstract
Various molecular triggers define heterogeneous subsets of gastrointestinal stromal tumors (GISTs), differing in clinical behavior and drug sensitivity. KIT/PDGFRA-wild-type GISTs, including those succinate dehydrogenase (SDH)-deficient, are overall unresponsive to the tyrosine kinase inhibitors commonly used, fostering the development of specific alternative therapeutic strategies. Epigenetic inactivation of O6-methylguanine-DNA methyltransferase (MGMT) through promoter methylation leads to effectiveness of alkylating agents in several human cancers. SDH-deficient GISTs typically feature widespread DNA methylation. However, the actual occurrence of MGMT methylation in these tumors, potentially predisposing them to respond to alkylating drugs, has not been investigated so far. Here we discuss the recent findings concerning the occurrence of MGMT methylation in different GIST subgroups, including SDH-deficient ones, as a premise for a possible reappraisal of alkylating agents specifically targeting these small, otherwise overall chemorefractory, GIST subgroups.
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Affiliation(s)
- Gloria Ravegnini
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Riccardo Ricci
- Department of Pathology, Università Cattolica del Sacro Cuore, Rome, Italy.,UOC di Anatomia Patologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
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Zheng L, Zhou D, Lu L, Liu Z, Fang L. Effects of CO 2 pneumoperitoneum on proliferation, apoptosis, and migration of gastrointestinal stromal tumor cells. Surg Endosc 2019; 33:3384-3395. [PMID: 30604263 DOI: 10.1007/s00464-018-06633-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 12/19/2018] [Indexed: 12/20/2022]
Abstract
BACKGROUND The purpose of the study was to investigate the proliferation and migration capability of human gastrointestinal stromal tumor line GIST-T1 after exposure to different pressures and times of CO2 pneumoperitoneum. METHODS We established simulated CO2 pneumoperitoneum environment in vitro and divided the human GIST cell GIST-T1 into open control group, 8 mmHg CO2 pneumoperitoneum treatment group and 15 mmHg CO2 pneumoperitoneum treatment group. Each group was divided into two subgroups respectively cultured for 1 h and 3 h. pH value of cell culture, cell growth curve, and cell cycle distribution of each group was measured. By application of scratch healing tests and Transwell chamber experiments, mobility ratio and number of cells through 8 µm membranes were measured to assess the migration ability of cells in each group after intervention. RESULTS Cell culture pH value of each subgroup in CO2 group decreased significantly after exposed in CO2 pneumoperitoneum (P < 0.01). The proliferation of GIST-T1 cells in 15 mmHg CO2 group was significantly inhibited early (1-2 days) (P < 0.05) and the proliferation of GIST-T1 cells in 8 mmHg CO2 1 h subgroup and 15 mmHg CO2 1 h subgroup was increased significantly late (4-6 days) (P < 0.05) after the interventions of CO2 pneumoperitoneum. The percentage of cells in G0-G1 phase increased, the percentage of S phase cells decreased (P < 0.01) in 1-h subgroup and 3-h subgroup of 15 mmHg CO2 group 24 h after exposure to CO2. The percentage of cells in S phase increased in 1-h subgroup of 8 mmHg CO2 group and decreased in 3-h subgroup of 15 mmHg CO2 group 72 h after exposure to CO2. In the Transwell chamber experiment, the cell number through 8-µm membrane increased significantly (P < 0.01) in 3-h subgroup of CO2 group compared to that in 3-h subgroup of control group. CONCLUSIONS The routine pressure and duration of CO2 pneumoperitoneum used in clinic did not promote the proliferation of gastrointestinal stromal tumors, but had a potential risk of increasing postoperative recurrence and distant metastasis.
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Affiliation(s)
- Lijun Zheng
- Department of General Surgery, Shanghai Tenth people's Hospital, Tongji University, No. 301 Middle Yanchang Road, Shanghai, 200072, People's Republic of China
| | - Donglei Zhou
- Department of General Surgery, Shanghai Tenth people's Hospital, Tongji University, No. 301 Middle Yanchang Road, Shanghai, 200072, People's Republic of China
| | - Liesheng Lu
- Department of General Surgery, Shanghai Tenth people's Hospital, Tongji University, No. 301 Middle Yanchang Road, Shanghai, 200072, People's Republic of China
| | - Zhongchen Liu
- Department of General Surgery, Shanghai Tenth people's Hospital, Tongji University, No. 301 Middle Yanchang Road, Shanghai, 200072, People's Republic of China
| | - Lin Fang
- Department of General Surgery, Shanghai Tenth people's Hospital, Tongji University, No. 301 Middle Yanchang Road, Shanghai, 200072, People's Republic of China.
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Subramamiam P, Ramasubbu C, Athiramu S, Arumugam S, Alagumuthu M. Pharmacological explorations of eco-friendly amide substituted (Z
)-β-enaminones as anti-breast cancer drugs. Arch Pharm (Weinheim) 2018; 352:e1800244. [DOI: 10.1002/ardp.201800244] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 10/27/2018] [Accepted: 10/30/2018] [Indexed: 12/28/2022]
Affiliation(s)
- Palaniraja Subramamiam
- Sigma-Aldrich Chemicals Pvt. Ltd.; (Subsidiary of Merck KGaA); Bangalore-560100 India
- Research and Development Center; Bharathiar University; Coimbatore India
| | | | - Selvaraj Athiramu
- Research and Development Center; Bharathiar University; Coimbatore India
| | - Sivakumar Arumugam
- Department of Biotechnology, School of Bio-Science and Technology; VIT University; Vellore India
| | - Manikandan Alagumuthu
- Department of Biotechnology, School of Bio-Science and Technology; VIT University; Vellore India
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Xue F, Liu Z, Xu J, Xu X, Chen X, Tian F. Neferine inhibits growth and migration of gastrointestinal stromal tumor cell line GIST-T1 by up-regulation of miR-449a. Biomed Pharmacother 2018; 109:1951-1959. [PMID: 30551450 DOI: 10.1016/j.biopha.2018.11.029] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Revised: 10/30/2018] [Accepted: 11/06/2018] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Gastrointestinal stromal tumor (GIST) threatens the health of middle-aged and older people with high recurrence rate and low survival rate. In this study, Neferin (Nef) was hoped to control growth and migration of GIST cell line GIST-T1. METHODS Cell viability, proliferation, apoptosis, and migration were determined by cell counting kit-8 (CCK-8) assay, bromodeoxyuridine (BrdU) assay, Annexin V-FITC/PI double staining method, and Transwell assay, respectively. The expression level of miR-449a was determined by qRT-PCR. Cell transfection was conducted to alter the expression level of miR-449a. Protein expression levels of key factors involved in cell cycle, cell apoptosis, cell migration, PI3K/AKT pathway and Notch pathways were analyzed by western boltting. RESULTS Nef significantly inhibited GIST-T1 cell viability, proliferation, migration, but promoted cell apoptosis. The expression level of miR-449a was up-regulated in GIST-T1 cells after Nef treatment. Suppression of miR-449a reversed the Nef-induced GIST-T1 cell proliferation and migration inhibition, as well as cell apoptosis. Importantly, Nef inactivated PI3K/AKT and Notch pathways in GIST-T1 cells by up-regulating miR-449a. Inhibitors of PI3K/AKT and Notch pathways notably reversed the effects of Nef + miR-449a inhibitor on GIST-T1 cell proliferation, apoptosis and migration. Besides, Nef also suppressed human gastric cancer SGC7901 cell migration and induced cell apoptosis. CONCLUSION Nef suppressed growth and migration of GIST-T1 cells possibly via up-regulation of miR-449a and then inactivation of PI3K/AKT and Notch pathways.
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Affiliation(s)
- Fangxi Xue
- Department of Gastroenterology, Linyi Central Hospital, Linyi, 276400, China
| | - Zhaoxia Liu
- Department of Gastroenterology, Linyi Central Hospital, Linyi, 276400, China
| | - Jian Xu
- Department of Gastroenterology, Linyi Central Hospital, Linyi, 276400, China
| | - Xiaoguang Xu
- Department of Gastroenterology, Linyi Central Hospital, Linyi, 276400, China
| | - Xingtian Chen
- Department of Gastroenterology, Linyi Central Hospital, Linyi, 276400, China
| | - Feng Tian
- Department of Gastroenterology, Linyi Central Hospital, Linyi, 276400, China.
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Aggile K, Alagumuthu M, Mundre RS, Napoleon AA. Synthesis of Substituted Quinolinyl Ether-based Inhibitors of PI3K as Potential Anticancer Agents. J Heterocycl Chem 2018. [DOI: 10.1002/jhet.3202] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Kadirappa Aggile
- School of Advanced Sciences, Department of Chemistry; VIT University; Vellore Tamil Nadu 632014 India
- Chemical Research Department, API R&D Centre; Micro Labs Ltd; Bommasandra Bangalore Karnataka 560105 India
| | - Manikandan Alagumuthu
- Department of Biotechnology, School of Bio-Science and Technology; VIT University; Vellore Tamil Nadu 632014 India
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Wang Y, Li J, Kuang D, Wang X, Zhu Y, Xu S, Chen Y, Cheng H, Zhao Q, Duan Y, Wang G. miR-148b-3p functions as a tumor suppressor in GISTs by directly targeting KIT. Cell Commun Signal 2018; 16:16. [PMID: 29661252 PMCID: PMC5902930 DOI: 10.1186/s12964-018-0228-z] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Accepted: 04/06/2018] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Gain-of-function mutations and overexpression of KIT are characteristic features of gastrointestinal stromal tumor (GIST). Dysregulation in miRNA expression may lead to KIT overexpression and tumorigenesis. METHODS miRNA microarray analysis and real-time PCR were used to determine the miRNA expression profiles in a cohort of 69 clinical samples including 50 CD117IHC+/KITmutation GISTs and 19 CD117IHC-/wild-type GISTs. GO enrichment and KEGG pathway analyses were performed to reveal the predicted targets of the dysregulated miRNAs. Of the dysregulated miRNAs whose expression was inversely correlated with that of KIT miRNAs were predicted by bioinformatics analysis and confirmed by luciferase reporter assay. Cell counting kit-8 (CCK-8) and flow cytometry were used to measure the cell proliferation, cycle arrest and apoptosis. Wound healing and transwell assays were used to evaluate migration and invasion. A xenograft BALB/c nude mouse model was applied to investigate the tumorigenesis in vivo. Western blot and qRT-PCR were used to investigate the protein and mRNA levels of KIT and its downstream effectors including ERK, AKT and STAT3. RESULTS Of the six miRNAs whose expression was inversely correlated with that of KIT, we found that miR-148b-3p was significantly downregulated in the CD117IHC+/KITmutation GIST cohort. This miRNA was subsequently found to inhibit proliferation, migration and invasion of GIST882 cells. Mechanistically, miR-148b-3p was shown to regulate KIT expression through directly binding to the 3'-UTR of the KIT mRNA. Restoration of miR-148b-3p expression in GIST882 cells led to reduced expression of KIT and the downstream effectors proteins ERK, AKT and STAT3. However, overexpression of KIT reversed the inhibitory effect of miR-148b-3p on cell proliferation, migration and invasion. Furthermore, we found that reduced miR-148b-3p expression correlated with poor overall survival (OS) and disease-free survival (DFS) in GIST patients. CONCLUSION miR-148b-3p functions as an important regulator of KIT expression and a potential prognostic biomarker for GISTs.
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Affiliation(s)
- Yu Wang
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Dadao, Wuhan, 430030, People's Republic of China
| | - Jun Li
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Dadao, Wuhan, 430030, People's Republic of China
- Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Dong Kuang
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Dadao, Wuhan, 430030, People's Republic of China
| | - Xiaoyan Wang
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Dadao, Wuhan, 430030, People's Republic of China
| | - Yuanli Zhu
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Dadao, Wuhan, 430030, People's Republic of China
| | - Sanpeng Xu
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Dadao, Wuhan, 430030, People's Republic of China
| | - Yaobing Chen
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Dadao, Wuhan, 430030, People's Republic of China
| | - Henghui Cheng
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Dadao, Wuhan, 430030, People's Republic of China
| | - Qiu Zhao
- Department of Gastroenterology, Zhongnan Hospital, Wuhan University, Wuhan, 430071, People's Republic of China
| | - Yaqi Duan
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Dadao, Wuhan, 430030, People's Republic of China.
- Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
| | - Guoping Wang
- Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Dadao, Wuhan, 430030, People's Republic of China.
- Department of Pathology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
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Zhou Y, Chen J, Weng X, Lin G, Huang Z, Shui H. Establishment of a GIST-T1 gastrointestinal stromal tumour cell line resistant to imatinib mesylate. Oncol Lett 2018; 15:7589-7594. [PMID: 29740484 PMCID: PMC5934714 DOI: 10.3892/ol.2018.8283] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Accepted: 12/20/2017] [Indexed: 01/13/2023] Open
Abstract
In the present study, imatinib mesylate (IM) was used to induce resistance in the gastrointestinal stromal tumour (GIST) cell line, GIST-T1, to establish a stable resistant cell line. The growth characteristics and expression profile of the established cell line were compared with those of the parental cell line. Additionally, the resistance mechanism of the gastrointestinal stromal tumours was preliminarily investigated. The GIST-T1 cells were cultured in vitro, and the drug was administered in the logarithmic phase of cell growth using intermittent dosing with increasing concentrations to obtain a drug-resistant cell line by repeated induction. Differences in the biological behaviours of the parental cells and drug-resistant cells were examined, and changes in the expression profiles were compared in the two cell lines. The results showed that the IM-resistant GIST-T1 cell line (GIST-T1 IR) was successfully established. Analysis of the biological behaviours of the two cell lines revealed that the average doubling times of the parental cells and drug-resistant cells were 26.59 and 33.63 h, respectively. The results of a scratch migration assay revealed that the migration ability was enhanced in the GIST-T1 IR cells. The results of CCK-8 detection indicated that the half maximal inhibitory concentration values of the two types of cells were 10.5 and 42.0 µM, respectively, which represented an increase of ~4-fold in the GIST-T1 IR cells. Flow cytometric cell cycle analysis indicated that the numbers of cells in the G0/G1, S and G2 phases increased following the induction treatment. Taken together, an IM-resistant GIST T1 cell line was successfully established, which opens novel avenues for individualized tumour chemotherapy.
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Affiliation(s)
- Yongjian Zhou
- Department of Gastric Surgery, Union Hospital of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Jiabi Chen
- Department of Urinary Surgery, The Second Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
| | - Xiaoyuan Weng
- Department of Gastric Surgery, Union Hospital of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Guosheng Lin
- Department of Gastric Surgery, Union Hospital of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
| | - Zicheng Huang
- Department of Digestive Medicine, Quanzhou First Hospital, Quanzhou, Fujian 362000, P.R. China
| | - Hanli Shui
- Department of Gastric Surgery, Union Hospital of Fujian Medical University, Fuzhou, Fujian 350001, P.R. China
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Expression and phosphorylation of FOXO1 influences cell proliferation and apoptosis in the gastrointestinal stromal tumor cell line GIST-T1. Exp Ther Med 2018; 15:3197-3202. [PMID: 29545835 PMCID: PMC5840899 DOI: 10.3892/etm.2018.5853] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Accepted: 07/27/2017] [Indexed: 12/28/2022] Open
Abstract
The mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) pathways are activated during pathogenesis of gastrointestinal stromal tumors (GISTs). Forkhead box protein O1 (FOXO1) is a transcription factor regulated by the MAPK and PI3K pathways and is associated with multiple metabolic reactions. The present study aims to investigate the association of FOXO1 with cell proliferation and apoptosis in the cell line, GIST-T1. Cell counting kit-8 assay revealed that cell growth was inhibited by the PI3K inhibitor, LY294002, and/or MAPK inhibitor, UO126. Western blotting demonstrated that the expression of p-FOXO1 and B-cell lymphoma 2 (Bcl2) were significantly reduced, whereas the expression of Bcl-2-associated X protein was significantly increased following treatment with LY294002 and/or UO126 (all P<0.05). However, no significant change was revealed in the level of total FOXO1. Flow cytometry revealed that apoptosis was significantly increased by the pathway inhibitors (P<0.05). Specifically, the proportion of cells in the G1 phase was increased whereas the proportion in the S phase was reduced. The changes of protein expression and cell apoptosis were more evident in the LY294002 + UO126 group than in either single-inhibitor group. The results indicated that FOXO1 was able to affect cell proliferation, apoptosis and the cell cycle of GISTs. The regulation of FOXO1 was part of the PI3K and MAPK signaling network, while this regulation was mostly activated by phosphorylation of FOXO1.
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Suvarna V, Murahari M, Khan T, Chaubey P, Sangave P. Phytochemicals and PI3K Inhibitors in Cancer-An Insight. Front Pharmacol 2017; 8:916. [PMID: 29311925 PMCID: PMC5736021 DOI: 10.3389/fphar.2017.00916] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Accepted: 11/30/2017] [Indexed: 12/11/2022] Open
Abstract
In today's world of modern medicine and novel therapies, cancer still remains to be one of the prime contributor to the death of people worldwide. The modern therapies improve condition of cancer patients and are effective in early stages of cancer but the advanced metastasized stage of cancer remains untreatable. Also most of the cancer therapies are expensive and are associated with adverse side effects. Thus, considering the current status of cancer treatment there is scope to search for efficient therapies which are cost-effective and are associated with lesser and milder side effects. Phytochemicals have been utilized for many decades to prevent and cure various ailments and current evidences indicate use of phytochemicals as an effective treatment for cancer. Hyperactivation of phosphoinositide 3-kinase (PI3K) signaling cascades is a common phenomenon in most types of cancers. Thus, natural substances targeting PI3K pathway can be of great therapeutic potential in the treatment of cancer patients. This chapter summarizes the updated research on plant-derived substances targeting PI3K pathway and the current status of their preclinical studies and clinical trials.
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Affiliation(s)
- Vasanti Suvarna
- Department of Pharmaceutical Chemistry and Quality Assurance, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Mumbai, India
| | - Manikanta Murahari
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, M.S Ramaiah University of Applied Sciences, Bangalore, India
| | - Tabassum Khan
- Department of Pharmaceutical Chemistry and Quality Assurance, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Mumbai, India
| | - Pramila Chaubey
- Department of Pharmaceutics, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, Mumbai, India
| | - Preeti Sangave
- Department of Pharmaceutical Sciences, School of Pharmacy and Technology Management, SVKM's NMIMS, Mumbai, India
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Wozniak A, Gebreyohannes YK, Debiec-Rychter M, Schöffski P. New targets and therapies for gastrointestinal stromal tumors. Expert Rev Anticancer Ther 2017; 17:1117-1129. [PMID: 29110548 DOI: 10.1080/14737140.2017.1400386] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION The majority of gastrointestinal stromal tumors (GIST) are driven by an abnormal receptor tyrosine kinase (RTK) signaling, occurring mainly due to somatic mutations in KIT or platelet derived growth factor receptor alpha (PDGFRA). Although the introduction of tyrosine kinase inhibitors (TKIs) has revolutionized therapy for GIST patients, with time the vast majority of them develop TKI resistance. Advances in understanding the molecular background of GIST resistance allows for the identification of new targets and the development of novel strategies to overcome or delay its occurrence. Areas covered: The focus of this review is on novel, promising therapeutic approaches to overcome heterogeneous resistance to registered TKIs. These approaches involve new TKIs, including drugs specific for a mutated form of KIT/PDGFRA, drugs with inhibitory effect against multiple RTKs, compounds targeting dysregulated downstream signaling pathways, drugs affecting KIT expression and degradation, inhibitors of cell cycle, and immunotherapeutics. Expert commentary: As the resistance to standard TKI treatment can be heterogeneous, a combinational approach for refractory GIST could be beneficial. Moreover, the understanding of the molecular background of resistant disease would allow development of a more personalized approach for these patients and their response to targeted therapy could be monitored closely using 'liquid biopsy'.
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Affiliation(s)
- Agnieszka Wozniak
- a Laboratory of Experimental Oncology, Department of Oncology , KU Leuven , Leuven , Belgium
| | | | | | - Patrick Schöffski
- a Laboratory of Experimental Oncology, Department of Oncology , KU Leuven , Leuven , Belgium.,c Department of General Medical Oncology , University Hospitals Leuven, Leuven Cancer Institute , Leuven , Belgium
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Mariño-Enríquez A, Bovée JVMG. Molecular Pathogenesis and Diagnostic, Prognostic and Predictive Molecular Markers in Sarcoma. Surg Pathol Clin 2017; 9:457-73. [PMID: 27523972 DOI: 10.1016/j.path.2016.04.009] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Sarcomas are infrequent mesenchymal neoplasms characterized by notable morphological and molecular heterogeneity. Molecular studies in sarcoma provide refinements to morphologic classification, and contribute diagnostic information (frequently), prognostic stratification (rarely) and predict therapeutic response (occasionally). Herein, we summarize the major molecular mechanisms underlying sarcoma pathogenesis and present clinically useful diagnostic, prognostic and predictive molecular markers for sarcoma. Five major molecular alterations are discussed, illustrated with representative sarcoma types, including 1. the presence of chimeric transcription factors, in vascular tumors; 2. abnormal kinase signaling, in gastrointestinal stromal tumor; 3. epigenetic deregulation, in chondrosarcoma, chondroblastoma, and other tumors; 4. deregulated cell survival and proliferation, due to focal copy number alterations, in dedifferentiated liposarcoma; 5. extreme genomic instability, in conventional osteosarcoma as a representative example of sarcomas with highly complex karyotype.
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Affiliation(s)
- Adrián Mariño-Enríquez
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.
| | - Judith V M G Bovée
- Department of Pathology, Leiden University Medical Center, Albinusdreef 2, Leiden 2333 ZA, The Netherlands
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Zhu CZ, Liu D, Kang WM, Yu JC, Ma ZQ, Ye X, Li K. Ghrelin and gastrointestinal stromal tumors. World J Gastroenterol 2017; 23:1758-1763. [PMID: 28348480 PMCID: PMC5352915 DOI: 10.3748/wjg.v23.i10.1758] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Revised: 11/28/2016] [Accepted: 01/11/2017] [Indexed: 02/06/2023] Open
Abstract
Ghrelin, as a kind of multifunctional protein polypeptide, is mainly produced in the fundus of the stomach and can promote occurrence and development of many tumors, including gastrointestinal tumors, which has been proved by the relevant researches. Most gastrointestinal stromal tumors (GISTs, about 80%), as the most common mesenchymal tumor, also develop in the fundus. Scientific research has confirmed that ghrelin, its receptors and mRNA respectively can be found in GISTs, which demonstrated the existence of a ghrelin autocrine/paracrine loop in GIST tissues. However, no reports to date have specified the mechanism whether ghrelin can promote the occurrence and development of GISTs. Studies of pulmonary artery endothelial cells in a low-oxygen environment and cardiac muscle cells in an ischemic environment have shown that ghrelin can activate the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway. Moreover, some studies of GISTs have confirmed that activation of the PI3K/AKT/mTOR pathway can indeed promote the growth and progression of GISTs. Whether ghrelin is involved in the development or progression of GISTs through certain pathways remains unknown. Can we find a new target for the treatment of GISTs? This review explores and summaries the relationship among ghrelin, the PI3K/AKT/mTOR pathway and the development of GISTs.
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Sankhala KK. Clinical development landscape in GIST: from novel agents that target accessory pathways to revisiting non-targeted therapies. Expert Opin Investig Drugs 2017; 26:427-443. [PMID: 28267385 DOI: 10.1080/13543784.2017.1303045] [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: 10/20/2022]
Abstract
INTRODUCTION Activating mutations in the genes encoding the tyrosine receptor kinases KIT and platelet-derived growth factor receptor occur in 85%-90% of patients with gastrointestinal stromal tumors (GIST). Although imatinib and other tyrosine kinase inhibitors have revolutionized the treatment of GIST, most patients progress within a few years. Areas covered: Monoclonal antibodies and small-molecule inhibitors targeting specific signaling pathways or proteins associated with resistance to existing treatments are being explored as alternative treatment approaches for GIST. Other alternative approaches include inhibiting more general regulators of protein folding, chromatin packaging, and cell-cycle regulation; nontargeted approaches are also being evaluated in select patient populations. This review summarizes preclinical and clinical data from agents using these accessory pathways. Expert opinion: As we learn more about GIST biology, it is becoming clear that treatment strategies will become more personalized, as reflected by the fact that several trials are enrolling specific subpopulations of patients with GIST. Going forward, researchers should evaluate these new drugs alone or in combination with other types of drugs to better meet patient needs.
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Affiliation(s)
- Kamalesh K Sankhala
- a Translational and Clinical Research , Sarcoma Oncology Center , Santa Monica , CA , USA
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Alagumuthu M, Arumugam S. Molecular explorations of substituted 2-(4-phenylquinolin-2-yl) phenols as phosphoinositide 3-kinase inhibitors and anticancer agents. Cancer Chemother Pharmacol 2017; 79:389-397. [PMID: 28054203 DOI: 10.1007/s00280-016-3227-z] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 12/12/2016] [Indexed: 01/22/2023]
Abstract
PURPOSE Substituted 2-(4-phenylquinolin-2-yl) phenols (PQPDs) emerged as the inhibitors of phosphoinositide 3-kinase (PI3K) and anticancer agents. METHOD PI3K inhibition was assessed by competitive ELISA. Anticancer activity was evaluated against breast cancer (MCF-7), skin cancer (G-361), and colon cancer (HCT 116) cell lines. RESULTS In PI3 Kinase assay, PQPDs 4c, 4d, and 4k were inactive with IC50 >5 µM. IC50 for 4a, 4b, 4f-h, and 4j was ≥0.05 µM. Rest PQPDs IC50 was <1.0 µM. Anticancer activity found selective toward breast cancer (MCF-7); 4a, 4b, and 4j were showed excellent inhibitory (73.95, 68.36, and 70.06%) and IC50 1.16 µM (4a), 2.07 µM (4b), 1.021 µM (4f) and 1.981 µM (4j) while the standard (Doxorubicin) found with IC50 1.812 µM (72% inhibition). PQPDs were docked into the active site of PI3 Kinase p110α (PDB ID: 2RD0). Docking results suggested the hydrophobic interactions in PI3K binding pocket conquered affinity of the most favorable binding ligands [4a, 4b: inhibitory constant (ki) = 53.33, 41.23 pM]. CONCLUSION PI3K assay and cancer cell line experimental results ensured that the inhibitory and anticancer activity potentials of PQPDs are more selective toward breast cancer treatments. PQPDs 4a, 4b, 4f, 4g, and 4j were displayed potent PI3 Kinase and anticancer activities. SAR studies demonstrated PQPDs as the PI3K precise inhibitors with the impending to treat various cancers.
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Affiliation(s)
- Manikandan Alagumuthu
- Department of Biotechnology, School of Bio-Science and Technology, VIT University, Vellore, Tamil Nadu, 632014, India
| | - Sivakumar Arumugam
- Department of Biotechnology, School of Bio-Science and Technology, VIT University, Vellore, Tamil Nadu, 632014, India.
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Gu ML, Wang YM, Zhou XX, Yao HP, Zheng S, Xiang Z, Ji F. An inhibitor of the acetyltransferases CBP/p300 exerts antineoplastic effects on gastrointestinal stromal tumor cells. Oncol Rep 2016; 36:2763-2770. [PMID: 27633918 DOI: 10.3892/or.2016.5080] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Accepted: 08/16/2016] [Indexed: 11/06/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasm featured by activated mutations of KIT and PDGFRA. Although overall survival rates have greatly improved by the development of receptor tyrosine kinase inhibitors, most patients ultimately acquire resistance due to secondary mutations of KIT or PDGFRA. Inhibition of the histone acetyltransferases (HATs) CREB‑binding protein (CBP) and p300 results in antineoplastic effects in various cancers. To determine whether CBP/p300 can serve as an antineoplastic target for GISTs, specific short interfering RNA sequences and the selective HAT inhibitor C646 were administered to GIST882 cells. Cell viability, apoptosis and the cell cycle were analysed using the Cell Counting Kit-8, a caspase-3/7 activity assay or Annexin V-fluorescein isothiocyanate/propidium iodide (PI) staining and PI staining. Gene and protein expression levels were measured by quantitative real-time polymerase chain reaction and western blotting, respectively. Transcriptional blockage of CBP, rather than p300, resulted in suppression of cell proliferation. Interestingly, both CBP and p300 depletion enhanced caspase-3/7 activity. A lack of CBP and p300 caused ETS translocation variant 1 (ETV1) downregulation and KIT inhibition in GIST cells. Nevertheless, the absence of CBP, not p300, leads to extracellular signal-regulated kinase 1/2 inactivation and c-Jun NH2-terminal kinase activation, suggesting a more crucial role for CBP than p300 in cell proliferation and survival. Furthermore, proliferation of GIST cells was reduced by administration of C646, a selective HAT inhibitor for CBP/p300. Apoptosis induction and cell cycle arrest were detected after exposure to C646, indicating that its antitumor activities were supported by its antiproliferative and proapoptotic effects. Additionally, C646 treatment attenuated ETV1 protein expression and inactivated KIT-dependent pathways. Taken together, the present study suggests that CBP/p300 may serve as novel antineoplastic targets and that use of the selective HAT inhibitor C646 is a promising antitumor strategy for GISTs.
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Affiliation(s)
- Meng-Li Gu
- Department of Gastroenterology, The First Affiliated Hospital of Medical College of Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Ya-Mei Wang
- Department of Gastroenterology, The First Affiliated Hospital of Medical College of Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Xin-Xin Zhou
- Department of Gastroenterology, The First Affiliated Hospital of Medical College of Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Hang-Ping Yao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Song Zheng
- Department of Oncology, Hangzhou Cancer Hospital, Hangzhou First People's Hospital, Hangzhou, Zhejiang 310006, P.R. China
| | - Zun Xiang
- Department of Gastroenterology, The First Affiliated Hospital of Medical College of Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
| | - Feng Ji
- Department of Gastroenterology, The First Affiliated Hospital of Medical College of Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
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Li F, Tao Y, Qiao Y, Li K, Jiang Y, Cao C, Ren S, Chang X, Wang X, Wang Y, Xie Y, Dong Z, Zhao J, Liu K. Eupatilin inhibits EGF-induced JB6 cell transformation by targeting PI3K. Int J Oncol 2016; 49:1148-54. [DOI: 10.3892/ijo.2016.3600] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Accepted: 06/17/2016] [Indexed: 11/05/2022] Open
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Zook P, Pathak HB, Belinsky MG, Gersz L, Devarajan K, Zhou Y, Godwin AK, von Mehren M, Rink L. Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor. Clin Cancer Res 2016; 23:171-180. [PMID: 27370604 DOI: 10.1158/1078-0432.ccr-16-0529] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Revised: 05/31/2016] [Accepted: 06/16/2016] [Indexed: 12/30/2022]
Abstract
PURPOSE Gastrointestinal stromal tumors (GIST) generally harbor activating mutations in the receptor tyrosine kinase KIT or in the related platelet-derived growth factor receptor alpha (PDGFRA). GIST treated with imatinib mesylate or second-line therapies that target mutant forms of these receptors generally escape disease control and progress over time. Inhibiting additional molecular targets may provide more substantial disease control. Recent studies have implicated the PI3K/AKT pathway in the survival of imatinib mesylate-resistant GIST cell lines and tumors. EXPERIMENTAL DESIGN Here, we performed in vitro and in vivo studies evaluating the novel combination of imatinib mesylate with the AKT inhibitor MK-2206 in GIST. Whole-transcriptome sequencing (WTS) of xenografts was performed to explore the molecular aspects of tumor response to this novel combination and to potentially identify additional therapeutic targets in GIST. RESULTS This drug combination demonstrated significant synergistic effects in a panel of imatinib mesylate-sensitive and -resistant GIST cell lines. Furthermore, combination therapy provided significantly greater efficacy, as measured by tumor response and animal survival, in imatinib mesylate-sensitive GIST xenografts as compared with treatment with imatinib mesylate or MK-2206 alone. WTS implicated two neural genes, brain expressed X-linked 1 and neuronal pentraxin I, whose expression was significantly upregulated in combination-treated tumors compared with tumors treated with the two monotherapies. CONCLUSIONS These studies provide strong preclinical justification for combining imatinib mesylate with an AKT inhibitor as a front-line therapy in GIST. In addition, the WTS implicated the BCL-2/BAX/BAD apoptotic pathway as a potential mechanism for this enhanced combination effect. Clin Cancer Res; 23(1); 171-80. ©2016 AACR.
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Affiliation(s)
- Phillip Zook
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
| | - Harsh B Pathak
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Martin G Belinsky
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
| | - Lawrence Gersz
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
| | - Karthik Devarajan
- Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
| | - Yan Zhou
- Department of Biostatistics and Bioinformatics, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
| | - Andrew K Godwin
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Margaret von Mehren
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
| | - Lori Rink
- Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA
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30
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Schmitt MW, Loeb LA, Salk JJ. The influence of subclonal resistance mutations on targeted cancer therapy. Nat Rev Clin Oncol 2016; 13:335-47. [PMID: 26483300 PMCID: PMC4838548 DOI: 10.1038/nrclinonc.2015.175] [Citation(s) in RCA: 177] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Clinical oncology is being revolutionized by the increasing use of molecularly targeted therapies. This paradigm holds great promise for improving cancer treatment; however, allocating specific therapies to the patients who are most likely to derive a durable benefit continues to represent a considerable challenge. Evidence continues to emerge that cancers are characterized by extensive intratumour genetic heterogeneity, and that patients being considered for treatment with a targeted agent might, therefore, already possess resistance to the drug in a minority of cells. Indeed, multiple examples of pre-existing subclonal resistance mutations to various molecularly targeted agents have been described, which we review herein. Early detection of pre-existing or emerging drug resistance could enable more personalized use of targeted cancer therapy, as patients could be stratified to receive the therapies that are most likely to be effective. We consider how monitoring of drug resistance could be incorporated into clinical practice to optimize the use of targeted therapies in individual patients.
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Affiliation(s)
- Michael W Schmitt
- Departments of Biochemistry and Pathology, University of Washington, 1959 Northeast Pacific Street, Box 357705, Seattle, WA 98195, USA
- Division of Medical Oncology, Department of Medicine, University of Washington, 1959 Northeast Pacific Street, Box 357705, Seattle, WA 98195, USA
- Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Box 19024, Seattle, WA 98109, USA
| | - Lawrence A Loeb
- Departments of Biochemistry and Pathology, University of Washington, 1959 Northeast Pacific Street, Box 357705, Seattle, WA 98195, USA
| | - Jesse J Salk
- Departments of Biochemistry and Pathology, University of Washington, 1959 Northeast Pacific Street, Box 357705, Seattle, WA 98195, USA
- Division of Medical Oncology, Department of Medicine, University of Washington, 1959 Northeast Pacific Street, Box 357705, Seattle, WA 98195, USA
- Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Box 19024, Seattle, WA 98109, USA
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31
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McLoughlin J, Nodit L, Heidel RE, Van Meter S, Macy S, Kestler D. The clinical correlation of phosphatase and tensin homolog on chromosome 10, phosphorylation of AKT to an activated state, and odontogenic ameloblast-associated protein in gastrointestinal stromal tumors. J Surg Res 2016; 202:403-12. [PMID: 27229116 DOI: 10.1016/j.jss.2016.01.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2015] [Revised: 11/23/2015] [Accepted: 01/11/2016] [Indexed: 11/18/2022]
Abstract
BACKGROUND Approximately 15% of gastrointestinal stromal tumors (GISTs) will not respond to tyrosine kinase inhibitors and drug resistance can develop over time. For refractory tumors, additional therapies are needed. Odontogenic ameloblast-associated protein (ODAM) is expressed in some epithelial malignancies and can correlate with clinical outcomes. This study evaluated ODAM and its relationship to phosphatase and tensin homolog on chromosome 10 (PTEN) and phosphorylation of AKT to an activated state (pAKT) in GISTs. MATERIALS AND METHODS Ninety-five distinct tumor specimens from 79 patients were identified. Morphologic features and clinical data were recorded for all tumors. Risk of recurrence was calculated using the Memorial Sloan-Kettering nomogram. Immunohistochemistry was performed using antibodies to ODAM, PTEN, and pAKT. Immunoreactivity was assessed for both cytoplasmic and nuclear expression. Staining patterns were correlated with clinical outcomes. RESULTS Increasing cytoplasmic ODAM staining correlated with a lower recurrence score (P = 0.002), a lower mitotic rate (P = 0.0001), and smaller tumor size (P = 0.038). Increasing pAKT cytoplasmic staining correlated with a higher recurrence score (P = 0.037) and a higher mitotic rate (P = 0.036). ODAM and pAKT expression in the nucleus was associated with tumor origin. PTEN nuclear expression increased with increasing mitotic rate. pAKT expression increased in the cytoplasm and nucleus in high-risk tumors. CONCLUSIONS Risk of recurrence correlated with cytoplasmic expression of ODAM and pAKT, whereas nuclear expression did not predict recurrence. The staining pattern for ODAM and pAKT in the cytoplasm may further clarify the risk of recurrence beyond the available nomograms. The increased expression of pAKT in the cytoplasm and nucleus of high-risk tumors suggests a potential target for systemic therapy.
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Affiliation(s)
- James McLoughlin
- Department of Surgery, University of Tennessee Medical Center, Knoxville, Tennessee.
| | - Laurentia Nodit
- Department of Pathology, University of Tennessee Medical Center, Knoxville, Tennessee
| | - R Eric Heidel
- Department of Biostatistics, University of Tennessee Medical Center, Knoxville, Tennessee
| | - Stuart Van Meter
- Department of Pathology, University of Tennessee Medical Center, Knoxville, Tennessee
| | - Sallie Macy
- University of Tennessee Medical Center, Graduate School of Medicine, Knoxville, Tennessee
| | - Daniel Kestler
- University of Tennessee Medical Center, Graduate School of Medicine, Knoxville, Tennessee
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Li A, Ma S, Smith SM, Lee MK, Fischer A, Borok Z, Bellusci S, Li C, Minoo P. Mesodermal ALK5 controls lung myofibroblast versus lipofibroblast cell fate. BMC Biol 2016; 14:19. [PMID: 26984772 PMCID: PMC4793501 DOI: 10.1186/s12915-016-0242-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Accepted: 02/26/2016] [Indexed: 12/18/2022] Open
Abstract
Background Epithelial-mesenchymal cross talk is centerpiece in the development of many branched organs, including the lungs. The embryonic lung mesoderm provides instructional information not only for lung architectural development, but also for patterning, commitment and differentiation of its many highly specialized cell types. The mesoderm also serves as a reservoir of progenitors for generation of differentiated mesenchymal cell types that include αSMA-expressing fibroblasts, lipofibroblasts, endothelial cells and others. Transforming Growth Factor β (TGFβ) is a key signaling pathway in epithelial-mesenchymal cross talk. Using a cre-loxP approach we have elucidated the role of the TGFβ type I receptor tyrosine kinase, ALK5, in epithelial-mesenchymal cross talk during lung morphogenesis. Results Targeted early inactivation of Alk5 in mesodermal progenitors caused abnormal development and maturation of the lung that included reduced physical size of the sub-mesothelial mesoderm, an established source of specific mesodermal progenitors. Abrogation of mesodermal ALK5-mediated signaling also inhibited differentiation of cell populations in the epithelial and endothelial lineages. Importantly, Alk5 mutant lungs contained a reduced number of αSMApos cells and correspondingly increased lipofibroblasts. Elucidation of the underlying mechanisms revealed that through direct and indirect modulation of target signaling pathways and transcription factors, including PDGFRα, PPARγ, PRRX1, and ZFP423, ALK5-mediated TGFβ controls a process that regulates the commitment and differentiation of αSMApos versus lipofibroblast cell populations during lung development. Conclusion ALK5-mediated TGFβ signaling controls an early pathway that regulates the commitment and differentiation of αSMApos versus LIF cell lineages during lung development. Electronic supplementary material The online version of this article (doi:10.1186/s12915-016-0242-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Aimin Li
- Division of Newborn Medicine, Department of Pediatrics, LAC+USC Medical Center and Childrens Hospital Los Angeles, Keck School of Medicine of USC, Los Angeles, CA, 90033, USA
| | - Shudong Ma
- Division of Newborn Medicine, Department of Pediatrics, LAC+USC Medical Center and Childrens Hospital Los Angeles, Keck School of Medicine of USC, Los Angeles, CA, 90033, USA
| | - Susan M Smith
- Division of Newborn Medicine, Department of Pediatrics, LAC+USC Medical Center and Childrens Hospital Los Angeles, Keck School of Medicine of USC, Los Angeles, CA, 90033, USA
| | - Matt K Lee
- Division of Newborn Medicine, Department of Pediatrics, LAC+USC Medical Center and Childrens Hospital Los Angeles, Keck School of Medicine of USC, Los Angeles, CA, 90033, USA
| | - Ashley Fischer
- Division of Newborn Medicine, Department of Pediatrics, LAC+USC Medical Center and Childrens Hospital Los Angeles, Keck School of Medicine of USC, Los Angeles, CA, 90033, USA
| | - Zea Borok
- Will Rogers Institute Pulmonary Research Center, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Keck School of Medicine of USC, Los Angeles, CA, 90033, USA.,Hastings Center for Pulmonary Research, Keck School of Medicine of USC, Los Angeles, CA, 90033, USA
| | - Saverio Bellusci
- Division of Newborn Medicine, Department of Pediatrics, LAC+USC Medical Center and Childrens Hospital Los Angeles, Keck School of Medicine of USC, Los Angeles, CA, 90033, USA.,Excellence Cluster Cardio Pulmonary System, University Justus Liebig Giessen, Giessen, 39352, Germany.,Institute of Fundamental Medicine and Biology, Kazan Federal University, Kremlevskaya St 18, Kazan, 420008, Russia
| | - Changgong Li
- Division of Newborn Medicine, Department of Pediatrics, LAC+USC Medical Center and Childrens Hospital Los Angeles, Keck School of Medicine of USC, Los Angeles, CA, 90033, USA
| | - Parviz Minoo
- Division of Newborn Medicine, Department of Pediatrics, LAC+USC Medical Center and Childrens Hospital Los Angeles, Keck School of Medicine of USC, Los Angeles, CA, 90033, USA. .,Hastings Center for Pulmonary Research, Keck School of Medicine of USC, Los Angeles, CA, 90033, USA.
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Daragmeh J, Barriah W, Saad B, Zaid H. Analysis of PI3K pathway components in human cancers. Oncol Lett 2016; 11:2913-2918. [PMID: 27073576 DOI: 10.3892/ol.2016.4309] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Accepted: 02/16/2016] [Indexed: 12/26/2022] Open
Abstract
Recent advances in genomics, proteomics, cell biology and biochemistry of tumors have revealed new pathways that are aberrantly activated in numerous cancer types. However, the enormous amount of data available in this field may mislead scientists in focused research. As cancer cell growth and progression is often dependent upon the phosphoinositide 3-kinase (PI3K)/AKT pathway, there has been extensive research into the proteins implicated in the PI3K pathway. Using data available in the Human Protein Atlas database, the current study investigated the expression of 25 key proteins that are known to be involved with PI3K pathway activation in a distinct group of 20 cancer types. These proteins are AKTIP, ARP1, BAD, GSK3A, GSK3B, MERTK-1, PIK3CA, PRR5, PSTPIP2, PTEN, FOX1, RHEB, RPS6KB1, TSC1, TP53, BCL2, CCND1, WFIKKN2, CREBBP, caspase-9, PTK2, EGFR, FAS, CDKN1A and XIAP. The analysis revealed pronounced expression of specific proteins in distinct cancer tissues, which may have the potential to serve as targets for treatments and provide insights into the molecular basis of cancer.
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Affiliation(s)
- Jamila Daragmeh
- Faculty of Arts and Sciences, The Arab American University - Jenin, Jenin 11184, Palestine
| | - Waseim Barriah
- Qasemi Research Center, Al-Qasemi Academic College of Education, Baqa El-Gharbia 30100, Israel
| | - Bashar Saad
- Faculty of Arts and Sciences, The Arab American University - Jenin, Jenin 11184, Palestine; Qasemi Research Center, Al-Qasemi Academic College of Education, Baqa El-Gharbia 30100, Israel
| | - Hilal Zaid
- Faculty of Arts and Sciences, The Arab American University - Jenin, Jenin 11184, Palestine; Qasemi Research Center, Al-Qasemi Academic College of Education, Baqa El-Gharbia 30100, Israel
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Lasota J, Felisiak-Golabek A, Wasag B, Kowalik A, Zięba S, Chłopek M, Wang ZF, Coates T, Kopczynski J, Gozdz S, Sarlomo-Rikala M, Miettinen M. Frequency and clinicopathologic profile of PIK3CA mutant GISTs: molecular genetic study of 529 cases. Mod Pathol 2016; 29:275-82. [PMID: 26796526 PMCID: PMC7511989 DOI: 10.1038/modpathol.2015.160] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Revised: 12/06/2015] [Accepted: 12/07/2015] [Indexed: 02/06/2023]
Abstract
Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors usually driven by the mutational activation of receptor tyrosine kinases, KIT, or PDGFRA. Oncogenic activation of phosphatidylinositide-3-kinase (PI3K), a downstream effector in the KIT signaling pathway, has been identified in different types of cancer, with the PI3K 110α subunit encoded by PIK3CA being a common mutational target. In this study, the mutational hotspot in the PIK3CA kinase domain encoded by exon 20 was evaluated in 529 imatinib-naive GISTs using PCR amplification and Sanger sequencing. Eight mutations (two co-existing in one tumor) were identified. Subsequently, The cobas PIK3CA Mutation Test was employed to evaluate mutational hotspots in exons 1, 4, 7, and 9 in 119 PIK3CA exon 20-wild type tumors. In two cases, mutations in exons 1 and 9 were identified. In one GIST, previously undetected by Sanger sequencing, the exon 20 mutation was discovered. Altogether, eight primary and two metastatic GISTs carried PIK3CA mutations. The size of primary PIK3CA-mutant GISTs was ≥14 cm (mean size 17 cm), and mitotic activity varied from 0 to 72 per 50HPF (mean 5/50HPF). Follow-up data showed short survival in 6 of 7 studied cases. Detection of PIK3CA mutations in large or metastatic KIT-mutant GISTs may suggest that PIK3CA-mutant clones have a proliferative advantage during disease progression. Tyrosine kinase inhibitors have been successfully used in GIST treatment. However, resistance frequently develops due to secondary KIT mutations or activation of downstream to KIT signaling pathways, such as the PI3K/AKT/mTOR pathway. PIK3CA mutations similar to the ones detected in GISTs have been shown to cause such activation. Therefore, genotyping of PIK3CA in GISTs might help to pinpoint primary and metastatic tumors with the potential to develop resistance to tyrosine kinase inhibitors and guide therapy with PI3K inhibitors.
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Affiliation(s)
- Jerzy Lasota
- Laboratory of Pathology, National Cancer Institute (NCI), Bethesda, MD, USA
| | | | - Bartosz Wasag
- Department of Biology and Genetics, Medical University of Gdansk, Gdansk, Poland
| | - Artur Kowalik
- Department of Molecular Diagnostics, Holycross Cancer Center, Kielce, Poland
| | - Sebastian Zięba
- Department of Molecular Diagnostics, Holycross Cancer Center, Kielce, Poland
| | - Małgorzata Chłopek
- Department of Molecular Diagnostics, Holycross Cancer Center, Kielce, Poland
| | - Zeng-Feng Wang
- Laboratory of Pathology, National Cancer Institute (NCI), Bethesda, MD, USA
| | - Tiffany Coates
- Laboratory of Pathology, National Cancer Institute (NCI), Bethesda, MD, USA,Participant of NCI summer 2014 internship program
| | - Janusz Kopczynski
- Department of Surgical Pathology, Holycross Cancer Center, Kielce, Poland
| | - Stanislaw Gozdz
- Department of Clinical Oncology, Holycross Cancer Center, Kielce, Poland,Faculty of Health Sciences, The Jan Kochanowski University, Kielce, Poland
| | | | - Markku Miettinen
- Laboratory of Pathology, National Cancer Institute (NCI), Bethesda, MD, USA
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35
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Cancer stem cells in human digestive tract malignancies. Tumour Biol 2015; 37:7-21. [PMID: 26446457 DOI: 10.1007/s13277-015-4155-y] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Accepted: 09/23/2015] [Indexed: 12/18/2022] Open
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Expression of CD117, DOG-1, and IGF-1R in gastrointestinal stromal tumours - an analysis of 70 cases from 2004 to 2010. GASTROENTEROLOGY REVIEW 2015; 11:115-22. [PMID: 27350839 PMCID: PMC4916232 DOI: 10.5114/pg.2015.52587] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Accepted: 03/08/2015] [Indexed: 12/12/2022]
Abstract
Introduction Determination of the type of mutations in gastrointestinal stromal tumours (GIST) plays a major role in assessing the risk of progression of the disease, and also allows determination of the clinical management and treatment. More accurate GIST diagnosis is possible by using simultaneously various types of antibodies to immunohistochemistry methods in routine procedures. Aim To evaluate the expression of CD117, DOG-1, and IGF-1R in patients with gastrointestinal stromal tumours, and analysis of the impact of the examined protein expression on patient survival with emphasis on specific recognition and prognostication of these tumours. Material and methods The protein expression was analyzed in 70 patients who had undergone surgical treatment for mesenchymal tumours of the gastrointestinal tract, using the immunohistochemical method. Results Positive expression of CD117, DOG-1, and IGF1R included 95.71%, 88.57% and 11.43% of study GISTs, respectively. Statistical analysis showed positive significant correlation between DOG-1 expression and histological type of tumour (p = 0.024). Analysis of overall survival curves of 70 GIST patients according to expression of CD117, DOG-1, and IGF1R did not show a tendency towards longer survival of patients with positive expression (p > 0.05). Conclusions Predictive factors determining the survival time of patients are strongly associated with morphological features of tumours. A thorough analysis of each case plays a key role in predicting survival time of patients and may be a clue in targeting the therapeutic procedure.
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Abstract
OPINION STATEMENT The management of advanced gastrointestinal stromal tumor (GIST) has been dramatically altered by the development of tyrosine kinase inhibitors. The disease, which had a median overall survival of 12 months for patients with unresectable disease, now has a median survival approaching 5 or more years. The challenge faced clinically is how to care for patients when they have progressed on all approved therapies. Clinical trials evaluating the role of novel combination therapies with investigational agents that target AKT/PI3K pathways are of interest especially given the preclinical rationale available. The addition of an mTOR inhibitor can be tried as these are available, but requires care and monitoring for additional toxicities. With improved understanding of this disease, which we thought of as one biology, personalized therapies are being studied and tested and is particularly relevant for GIST that are less responsive to the standard kinase inhibitors, such as platelet-derived growth factor alpha (PDGFRA) D842V and wild-type/succinate dehydrogenase (SDH)-deficient GIST. IGF1R inhibitors as a class are not being developed because of the lack of significant efficacy in many clinical trials and the efficacy in WT GIST has been limited; to date drugs targeting VEGFR, such as sunitinib and regorafenib, appear to be the best agents available for this group of patients. The exciting findings seen with CTLA4 and PD-1/PD-L1 antibodies in melanoma and other solid tumors is exciting, especially because there is a growing body of evidence that such approaches have biologic rationale; clinical trials evaluating these agents are awaited with interest. Last, recent work has shed light on older agents that may have a role in GIST. Moving forward to test these agents alone or in combination with TKIs offers potentially new strategies for treating advanced disease.
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Affiliation(s)
- Natthapol Songdej
- Department of Medical Oncology and Hematology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
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Zhu JQ, Ou WB. Therapeutic targets in gastrointestinal stromal tumors. World J Transl Med 2015; 4:25-37. [DOI: 10.5528/wjtm.v4.i1.25] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2014] [Revised: 09/14/2014] [Accepted: 12/01/2014] [Indexed: 02/05/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common type of mesenchymal tumor of the gastrointestinal tract. The tumorigenesis of GISTs is driven by gain-of-function mutations in KIT or platelet-derived growth factor receptor α (PDGFRA), resulting in constitutive activation of the tyrosine kinase and its downstream signaling pathways. Oncogenic KIT or PDGFRA mutations are compelling therapeutic targets for the treatment of GISTs, and the KIT/PDGFRA inhibitor imatinib is the standard of care for patients with metastatic GISTs. However, most GIST patients develop clinical resistance to imatinib and other tyrosine kinase inhibitors. Five mechanisms of resistance have been characterized: (1) acquisition of a secondary point mutation in KIT or PDGFRA; (2) genomic amplification of KIT; (3) activation of an alternative receptor tyrosine kinase; (4) loss of KIT oncoprotein expression; and (5) wild-type GIST. Currently, sunitinib is used as a second-line treatment for patients after imatinib failure, and regorafenib has been approved for patients whose disease is progressing on both imatinib and sunitinib. Phase II/III trials are currently in progress to evaluate novel inhibitors and immunotherapies targeting KIT, its downstream effectors such as phosphatidylinositol 3-kinase, protein kinase B and mammalian target of rapamycin, heat shock protein 90, and histone deacetylase inhibitor. Other candidate targets have been identified, including ETV1, AXL, insulin-like growth factor 1 receptor, KRAS, FAS receptor, protein kinase c theta, ANO1 (DOG1), CDC37, and aurora kinase A. These candidates warrant clinical evaluation as novel therapeutic targets in GIST.
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DU Y, Zhang H, Jiang Z, Huang G, Lu W, Wang H. Expression of L1 protein correlates with cluster of differentiation 24 and integrin β1 expression in gastrointestinal stromal tumors. Oncol Lett 2015; 9:2595-2602. [PMID: 26137113 DOI: 10.3892/ol.2015.3096] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Accepted: 01/29/2015] [Indexed: 12/11/2022] Open
Abstract
The present study examined 66 cases of gastrointestinal stromal tumors (GISTs), 20 cases of smooth muscle tumors, 20 cases of schwannomas and 20 cases of normal gastric tissues in order to analyze the expression of L1, cluster of differentiation (CD)24 and integrin β1 by immunohistochemical staining. Patients were subjected to follow-up, and survival data were evaluated. L1 expression was detected in 57.6% of GIST cases; this was a significantly higher percentage compared with that found in the smooth muscle tumor cases or the normal control group. CD24 and integrin β1 were also expressed at significantly higher levels in the GIST cases than in the normal control group, although no significant difference was found in the expression levels of these proteins in smooth muscle tumor or schwannoma cases. These higher levels of L1 and integrin β1 expression were associated with an increased risk of invasive GIST, and were significantly positively correlated with Ki-67 expression. CD24 expression was not associated with the risk of GIST invasion or Ki-67 expression. There were positive correlations between L1, CD24 and integrin β1 expression; however, these had no significant association with patient survival. Therefore, L1 alone or in conjunction with CD24 (L1 + CD24), or integrin β1 (L1 + integrin β1) can be considered a valuable indicator for the differential diagnosis of GIST. Furthermore, L1 and integrin β1 can be used alone or in combination to evaluate the biological behavior of GISTs. Future studies are required to evaluate the prognostic value of these markers.
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Affiliation(s)
- Yue DU
- Department of Public Health, Tianjin Medical University, Tianjin 300070, P.R. China
| | - Haihong Zhang
- Department of Public Health, Tianjin Medical University, Tianjin 300070, P.R. China
| | - Zhongmin Jiang
- Department of Pathology, Tianjin Fifth Central Hospital, Tianjin 300450, P.R. China
| | - Guowei Huang
- Department of Public Health, Tianjin Medical University, Tianjin 300070, P.R. China
| | - Wenli Lu
- Department of Public Health, Tianjin Medical University, Tianjin 300070, P.R. China
| | - Hesheng Wang
- Department of Public Health, Tianjin Medical University, Tianjin 300070, P.R. China
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Subbiah V. Prospects and pitfalls of personalizing therapies for sarcomas: from children, adolescents, and young adults to the elderly. Curr Oncol Rep 2015; 16:401. [PMID: 25030655 DOI: 10.1007/s11912-014-0401-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Sarcomas are a heterogeneous class of tumors that affect all ages, from children, adolescents, and young adults to the elderly. Within this panoply of tumor subtypes lies the opportunity to bring to bear a vision of personalized medicine in which the fast-paced evolution from the "one gene, one test, one drug" approach to a comprehensive "panomic," multiplex, multianalyte method coupled with advances in bioinformatics platforms can unravel the biology of this disease. The increasingly enlarging repertoire of novel agents provides innumerable prospects in precision medicine. Personalized therapy covers the entire spectrum of cancer care, from risk factor assessment through prevention, risk reduction, therapy, follow-up after therapy, and survivorship care. Challenges remain in implementing the science of precision medicine in the clinic, including providing comprehensive multidisciplinary care and overcoming regulatory and economic hurdles, which must be facilitated within the collaborative framework of academia, industry, federal regulators, and third-party payers.
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Affiliation(s)
- Vivek Subbiah
- Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), Division of Cancer Medicine and Division of Pediatrics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA,
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Wang X, Li S. Protein mislocalization: mechanisms, functions and clinical applications in cancer. BIOCHIMICA ET BIOPHYSICA ACTA 2014; 1846:13-25. [PMID: 24709009 PMCID: PMC4141035 DOI: 10.1016/j.bbcan.2014.03.006] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/14/2013] [Revised: 02/20/2014] [Accepted: 03/27/2014] [Indexed: 12/21/2022]
Abstract
The changes from normal cells to cancer cells are primarily regulated by genome instability, which foster hallmark functions of cancer through multiple mechanisms including protein mislocalization. Mislocalization of these proteins, including oncoproteins, tumor suppressors, and other cancer-related proteins, can interfere with normal cellular function and cooperatively drive tumor development and metastasis. This review describes the cancer-related effects of protein subcellular mislocalization, the related mislocalization mechanisms, and the potential application of this knowledge to cancer diagnosis, prognosis, and therapy.
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Affiliation(s)
- Xiaohong Wang
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA
| | - Shulin Li
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
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Farid M, Ahn L, Brohl A, Cioffi A, Maki RG. The mechanistic target of rapamycin pathway in sarcomas: from biology to therapy. Expert Opin Orphan Drugs 2014. [DOI: 10.1517/21678707.2014.917951] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Liu S, Cui J, Liao G, Zhang Y, Ye K, Lu T, Qi J, Wan G. MiR-137 regulates epithelial-mesenchymal transition in gastrointestinal stromal tumor. Tumour Biol 2014; 35:9131-8. [PMID: 25027394 DOI: 10.1007/s13277-014-2177-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2014] [Accepted: 06/02/2014] [Indexed: 12/19/2022] Open
Abstract
Activation of the epithelial-to-mesenchymal transition (EMT) endows extraordinary invasive capability of cancer cells and causes of treatment failure and metastasis in gastrointestinal stromal tumor (GIST); however, the molecular mechanisms governing GIST invasion remain largely unknown. MicroRNAs (miRNAs) have been shown to play critical roles in cell motility and invasion, which promotes us to study the biological functions of miR-137 in the EMT of GIST. We have found that miR-137 was dramatically downregulated in clinical specimen of GIST. Using an in silico analysis approach, Twist1, a key regulator gene of EMT, has been identified as the target of miR-137. Quantitative RT-PCT and western blot were used to confirm that miR-137 directly targeted on Twist1 and repressed Twist1 expression in GIST-H1 human gastrointestinal stromal tumor cell line. Further, miR-137 was found to increase expression of E-cadherin and cytokeratin, but suppress expression of N-cadherin and vimentin. In vitro experiments have shown that miR-137 enhanced the epithelial cell morphology, decreased GIST cell migration, activated G1 cell cycle arrest, and induced cell apoptosis. These results suggest a novel mechanism that miR-137 regulates EMT and inhibits cell migration via Twist1 downregulation. Therefore, miR-137 may function as anti-migration and anti-metastasis in GIST and our study provides a potential approach for developing miR-137-based therapeutic strategy for GIST.
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Affiliation(s)
- Sheng Liu
- Department of Gastrointestinal Surgery, Xiangya Hospital of Central South University, Changsha, Hunan, 410008, China
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Reinke EN, Ekoue DN, Bera S, Mahmud N, Diamond AM. Translational regulation of GPx-1 and GPx-4 by the mTOR pathway. PLoS One 2014; 9:e93472. [PMID: 24691473 PMCID: PMC3972146 DOI: 10.1371/journal.pone.0093472] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Accepted: 03/05/2014] [Indexed: 02/02/2023] Open
Abstract
Glutathione peroxidase activity was previously determined to be elevated in lymphocytes obtained from patients treated with the Bcr-Abl kinase inhibitor imatinib mesylate. In order to expand upon this observation, the established chronic myelogenous leukemia cell lines KU812 and MEG-01 were treated with imatinib and the effect on several anti-oxidant proteins was determined. The levels of GPx-1 were significantly increased following treatment with imatinib. This increase was not due to altered steady-state mRNA levels, and appeared to be dependent on the expression of Bcr-Abl, as no increases were observed following imatinib treatment of cells that did not express the fusion protein. The nutrient-sensing signaling protein, mammalian target of rapamycin (mTOR), can be activated by Bcr-Abl and its activity regulates the translation of many different proteins. Treatment of those same cells used in the imatinib studies with rapamycin, an inhibitor of mTOR, resulted in elevated GPx-1 and GPx-4 protein levels independent of Bcr-Abl expression. These proteins all belong to the selenoprotein family of peptides that contain the UGA-encoded amino acid selenocysteine. Collectively, these data provide evidence of a novel means of regulating anti-oxidants of the selenoprotein family via the mTOR pathway.
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Affiliation(s)
- Emily N. Reinke
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Dede N. Ekoue
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Soumen Bera
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Nadim Mahmud
- Department of Medicine, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Alan M. Diamond
- Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, United States of America
- * E-mail:
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Fan R, Zhong J, Zheng S, Wang Z, Xu Y, Li S, Zhou J, Yuan F. MicroRNA-218 inhibits gastrointestinal stromal tumor cell and invasion by targeting KIT. Tumour Biol 2013; 35:4209-17. [PMID: 24375253 DOI: 10.1007/s13277-013-1551-z] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2013] [Accepted: 12/13/2013] [Indexed: 12/14/2022] Open
Abstract
The objectives of this study were to detect the expressions of microRNA-218 (miR-218) in human gastrointestinal stromal tumor (GIST) tissues and cells and explore its effects on the biological features of GIST-T1 cells and the expression of its target gene KIT, so as to provide new insights for GIST treatment. Using quantitative real-time polymerase chain reaction (qRT-PCR), we detected the expressions of miR-218 in the tissues and adjacent tissues of GIST and in the GIST cell lines including GIST882, GIST430, GIST48, and GIST-T1. Forty-eight hours after the miR-218 mimic was transfected into the GIST-T1 cells, the expression of miR-218 in the GIST-T1 cells was detected by qRT-PCR. The effect of miR-218 on the GIST-T1 cell viability was detected using MTT. The effect of miR-218 on the proliferation and apoptosis of GIST-T1 cell was analyzed using flow cytometry. Transwell invasion chamber was applied to detect the effect of miR-218 on the invasion of GIST-T1 cells. KIT was identified to be a target gene of miR-218 by the luciferase reporter enzyme system, and the effect of miR-218 on the expression of KIT protein in cells was determined using Western blotting. As shown by qRT-PCR, compared with that in the GIST adjacent tissue, the expressions of miR-218 in the tumor tissue and GIST cell lines were significantly decreased (P < 0.0001). Compared with the control group, the expression of miR-218 increased significantly in GIST-T1 cells transfected with miR-218 mimic for 48 h (P < 0.01). MTT showed that the cell viability decreased significantly after the overexpression of miR-218 in the GIST-T1 cells (P < 0.01). Flow cytometry showed that the cell proliferation index significantly declined after the overexpression of miR-218 (P < 0.01); meanwhile, the apoptosis of cells also significantly increased (P < 0.01). Detection using the Transwell invasion chamber showed that the number of cells passing through the Transwell chamber significantly dropped after the enhanced expression of miR-218 (P < 0.01). Luciferase reporter gene assay showed that, compared with the control group, the relative luciferase activity significantly declined in the miR-218 mimic transfection group (P < 0.01). Compared with the control group, the expression of KIT protein in the GIST-T1 cells transfected with miR-218 mimic for 48 h significantly decreased (P < 0.01). In conclusion, the expression of miR-218 decreases in human GIST tissue and cell lines. miR-218 can negatively regulate the expression of KIT protein and inhibit the proliferation and invasion of GIST cells. Treatment based on the enhanced expression of miR-218 may be a promising strategy for GIST.
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Affiliation(s)
- Rong Fan
- Department of Gastroenterology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Ruijin Er Rd, Shanghai, 200025, China
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Romano G. The role of the dysfunctional akt-related pathway in cancer: establishment and maintenance of a malignant cell phenotype, resistance to therapy, and future strategies for drug development. SCIENTIFICA 2013; 2013:317186. [PMID: 24381788 PMCID: PMC3870877 DOI: 10.1155/2013/317186] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/21/2013] [Accepted: 11/14/2013] [Indexed: 06/01/2023]
Abstract
Akt serine/threonine kinases, or PKB, are key players in the regulation of a wide variety of cellular activities, such as growth, proliferation, protection from apoptotic injuries, control of DNA damage responses and genome stability, metabolism, migration, and angiogenesis. The Akt-related pathway responds to the stimulation mediated by growth factors, cytokines, hormones, and several nutrients. Akt is present in three isoforms: Akt1, Akt2, and Akt3, which may be alternatively named PKB α , PKB β , and PKB γ , respectively. The Akt isoforms are encoded on three diverse chromosomes and their biological functions are predominantly distinct. Deregulations in the Akt-related pathway were observed in many human maladies, including cancer, cardiopathies, neurological diseases, and type-2 diabetes. This review discusses the significance of the abnormal activities of the Akt axis in promoting and sustaining malignancies, along with the development of tumor cell populations that exhibit enhanced resistance to chemo- and/or radiotherapy. This occurrence may be responsible for the relapse of the disease, which is unfortunately very often related to fatal consequences in patients.
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Affiliation(s)
- Gaetano Romano
- Department of Biology, College of Science and Technology, Temple University, Bio Life Science Building, Suite 456, 1900 N. 12th Street, Philadelphia, PA 19122, USA
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Abstract
Clinical trials with new drugs for chronic obstructive pulmonary disease (COPD) have been performed. Viruses exacerbate COPD and bacteria may play a part in severe COPD; therefore, antibiotic and antiviral approaches have a sound rationale. Antiinflammatory approaches have been studied. Advances in understanding the molecular basis of other processes have resulted in novel drugs to target reactive oxidant species, mucus, proteases, fibrosis, cachexia, and muscle wasting, and accelerated aging. Studies with monoclonal antibodies have been disappointing, highlighting the tendency for infections and malignancies during treatment. Promising future directions are lung regeneration with retinoids and stem cells.
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Affiliation(s)
- Clare L Ross
- Imperial Clinical Respiratory Research Unit (ICRRU), Biomedical Research Centre (BMRC), Centre for Respiratory Infection (CRI), National Heart and Lung Institute (NHLI), St Mary's Hospital, Imperial College, Praed Street, Paddington, London W2 INY, UK
| | - Trevor T Hansel
- Imperial Clinical Respiratory Research Unit (ICRRU), Biomedical Research Centre (BMRC), Centre for Respiratory Infection (CRI), National Heart and Lung Institute (NHLI), St Mary's Hospital, Imperial College, Praed Street, Paddington, London W2 INY, UK.
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48
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Akinleye A, Avvaru P, Furqan M, Song Y, Liu D. Phosphatidylinositol 3-kinase (PI3K) inhibitors as cancer therapeutics. J Hematol Oncol 2013; 6:88. [PMID: 24261963 PMCID: PMC3843585 DOI: 10.1186/1756-8722-6-88] [Citation(s) in RCA: 201] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2013] [Accepted: 11/12/2013] [Indexed: 02/08/2023] Open
Abstract
Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that regulate diverse cellular processes including proliferation, adhesion, survival, and motility. Dysregulated PI3K pathway signaling occurs in one-third of human tumors. Aberrantly activated PI3K signaling also confers sensitivity and resistance to conventional therapies. PI3K has been recognized as an attractive molecular target for novel anti-cancer molecules. In the last few years, several classes of potent and selective small molecule PI3K inhibitors have been developed, and at least fifteen compounds have progressed into clinical trials as new anticancer drugs. Among these, idelalisib has advanced to phase III trials in patients with advanced indolent non-Hodgkin's lymphoma and mantle cell lymphoma. In this review, we summarized the major molecules of PI3K signaling pathway, and discussed the preclinical models and clinical trials of potent small-molecule PI3K inhibitors.
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Affiliation(s)
| | | | | | | | - Delong Liu
- Division of Hematology/Oncology, Department of Medicine, New York Medical College and Westchester Medical Center, Valhalla, NY 10595, USA.
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