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      Current status and perspectives of patient-derived xenograft models in cancer research

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          Abstract

          Cancers remain a major public health problem worldwide, which still require profound research in both the basic and preclinical fields. Patient-derived xenograft (PDX) models are created when cancerous cells or tissues from patients’ primary tumors are implanted into immunodeficient mice to simulate human tumor biology in vivo, which have been extensively used in cancer research. The routes of implantation appeared to affect the outcome of PDX research, and there has been increasing applications of patient-derived orthotopic xenograft (PDOX) models. In this review, we firstly summarize the methodology to establish PDX models and then go over recent application and function of PDX models in basic cancer research on the areas of cancer characterization, initiation, proliferation, metastasis, and tumor microenvironment and in preclinical explorations of anti-cancer targets, drugs, and therapeutic strategies and finally give our perspectives on the future prospects of PDX models.

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          Most cited references113

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          Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases.

          The non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, has an important role in signal transduction downstream of growth factor receptor signalling and was the first reported oncogenic tyrosine phosphatase. Activating mutations of SHP2 have been associated with developmental pathologies such as Noonan syndrome and are found in multiple cancer types, including leukaemia, lung and breast cancer and neuroblastoma. SHP2 is ubiquitously expressed and regulates cell survival and proliferation primarily through activation of the RAS–ERK signalling pathway. It is also a key mediator of the programmed cell death 1 (PD-1) and B- and T-lymphocyte attenuator (BTLA) immune checkpoint pathways. Reduction of SHP2 activity suppresses tumour cell growth and is a potential target of cancer therapy. Here we report the discovery of a highly potent (IC50 = 0.071 μM), selective and orally bioavailable small-molecule SHP2 inhibitor, SHP099, that stabilizes SHP2 in an auto-inhibited conformation. SHP099 concurrently binds to the interface of the N-terminal SH2, C-terminal SH2, and protein tyrosine phosphatase domains, thus inhibiting SHP2 activity through an allosteric mechanism. SHP099 suppresses RAS–ERK signalling to inhibit the proliferation of receptor-tyrosine-kinase-driven human cancer cells in vitro and is efficacious in mouse tumour xenograft models. Together, these data demonstrate that pharmacological inhibition of SHP2 is a valid therapeutic approach for the treatment of cancers.
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            LncRNA-Dependent Mechanisms of Androgen Receptor-regulated Gene Activation Programs

            While recent studies indicated roles of long non-coding RNAs (lncRNAs) in physiologic aspects of cell-type determination and tissue homeostasis 1 yet their potential involvement in regulated gene transcription programs remain rather poorly understood. Androgen receptor (AR) regulates a large repertoire of genes central to the identity and behavior of prostate cancer cells 2 , and functions in a ligand-independent fashion in many prostate cancers when they become hormone refractory after initial androgen deprivation therapy 3 . Here, we report that two lncRNAs highly overexpressed in aggressive prostate cancer, PRNCR1 and PCGEM1, bind successively to the AR and strongly enhance both ligand-dependent and ligand-independent AR-mediated gene activation programs and proliferation in prostate cancer cells. Binding of PRNCR1 to the C-terminally acetylated AR on enhancers and its association with DOT1L appear to be required for recruitment of the second lncRNA, PCGEM1, to the DOT1L-mediated methylated AR N-terminus. Unexpectedly, recognition of specific protein marks by PCGEM1-recruited Pygopus2 PHD domain proves to enhance selective looping of AR-bound enhancers to target gene promoters in these cells. In “resistant” prostate cancer cells, these overexpressed lncRNAs can interact with, and are required for, the robust activation of both truncated and full length AR, causing ligand-independent activation of the AR transcriptional program and cell proliferation. Conditionally-expressed short hairpin RNA (shRNA) targeting of these lncRNAs in castration-resistant prostate cancer (CRPC) cell lines strongly suppressed tumor xenograft growth in vivo. Together, these results suggest that these overexpressed lncRNAs can potentially serve as a required component of castration-resistance in prostatic tumors.
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              Engineered CAR T Cells Targeting the Cancer-Associated Tn-Glycoform of the Membrane Mucin MUC1 Control Adenocarcinoma.

              Genetically modified T cells expressing chimeric antigen receptors (CARs) demonstrate robust responses against lineage restricted, non-essential targets in hematologic cancers. However, in solid tumors, the full potential of CAR T cell therapy is limited by the availability of cell surface antigens with sufficient cancer-specific expression. The majority of CAR targets have been normal self-antigens on dispensable hematopoietic tissues or overexpressed shared antigens. Here, we established that abnormal self-antigens can serve as targets for tumor rejection. We developed a CAR that recognized cancer-associated Tn glycoform of MUC1, a neoantigen expressed in a variety of cancers. Anti-Tn-MUC1 CAR T cells demonstrated target-specific cytotoxicity and successfully controlled tumor growth in xenograft models of T cell leukemia and pancreatic cancer. These findings demonstrate the therapeutic efficacy of CAR T cells directed against Tn-MUC1 and present aberrantly glycosylated antigens as a novel class of targets for tumor therapy with engineered T cells.
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                Author and article information

                Contributors
                Lai_yunxin@gibh.ac.cn
                Wei_xinru@gibh.ac.cn
                lin_shouheng@gibh.ac.cn
                Qin_le@gibh.ac.cn
                Cheng_lin@gibh.ac.cn
                li_peng@gibh.ac.cn
                Journal
                J Hematol Oncol
                J Hematol Oncol
                Journal of Hematology & Oncology
                BioMed Central (London )
                1756-8722
                12 May 2017
                12 May 2017
                2017
                : 10
                : 106
                Affiliations
                [1 ]ISNI 0000000119573309, GRID grid.9227.e, Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, , Chinese Academy of Sciences, ; Guangzhou, 510530 China
                [2 ]ISNI 0000000119573309, GRID grid.9227.e, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, , Chinese Academy of Sciences, ; Guangzhou, 510530 China
                [3 ]ISNI 0000 0000 8653 1072, GRID grid.410737.6, Department of Abdominal Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University of Guangzhou Medical University, , Guangzhou Medical University, ; Guangzhou, Guangdong 510095 China
                Article
                470
                10.1186/s13045-017-0470-7
                5427553
                28499452
                e68ce4d0-52eb-48a9-b535-3300080474c7
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 15 March 2017
                : 22 April 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81522002
                Award Recipient :
                Funded by: Strategic Priority Research Program of the Chinese Academy of Sciences
                Award ID: XDB19030205
                Award Recipient :
                Funded by: Natural Science Fund for Distinguished Young Scholars of Guangdong Province
                Award ID: 2014A030306028
                Award Recipient :
                Funded by: Guangdong Provincial Applied Science and Technology Research& Development Program
                Award ID: 2016B020237006
                Award Recipient :
                Funded by: Guangdong Provincial Outstanding Young Scholars Award
                Award ID: 2014TQ01R068
                Award Recipient :
                Funded by: Frontier and key technology innovation special grant from the Department of Science and Technology of Guangdong province
                Award ID: 2016B030229006
                Award Recipient :
                Funded by: the Guangdong Provincial Research and Commercialization Program
                Award ID: 2014B090901044
                Award Recipient :
                Funded by: Guangzhou Science Technology and Innovation Commission Project
                Award ID: 201504010016
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2017

                Oncology & Radiotherapy
                pdx models,basic,preclinical,cancer research,drugs
                Oncology & Radiotherapy
                pdx models, basic, preclinical, cancer research, drugs

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