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      Tumor Tissue Explant Culture of Patient-Derived Xenograft as Potential Prioritization Tool for Targeted Therapy

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          Abstract

          Despite of remarkable progress made in the head and neck cancer (HNC) therapy, the survival rate of this metastatic disease remain low. Tailoring the appropriate therapy to patients is a major challenge and highlights the unmet need to have a good preclinical model that will predict clinical response. Hence, we developed an accurate and time efficient drug screening method of tumor ex vivo analysis (TEVA) system, which can predict patient-specific drug responses. In this study, we generated six patient derived xenografts (PDXs) which were utilized for TEVA. Briefly, PDXs were cut into 2 × 2 × 2 mm 3 explants and treated with clinically relevant drugs for 24 h. Tumor cell proliferation and death were evaluated by immunohistochemistry and TEVA score was calculated. Ex vivo and in vivo drug efficacy studies were performed on four PDXs and three drugs side-by-side to explore correlation between TEVA and PDX treatment in vivo. Efficacy of drug combinations was also ventured. Optimization of the culture timings dictated 24 h to be the time frame to detect drug responses and drug penetrates 2 × 2 × 2 mm 3 explants as signaling pathways were significantly altered. Tumor responses to drugs in TEVA, significantly corresponds with the drug efficacy in mice. Overall, this low cost, robust, relatively simple and efficient 3D tissue-based method, employing material from one PDX, can bypass the necessity of drug validation in immune-incompetent PDX-bearing mice. Our data provides a potential rationale for utilizing TEVA to predict tumor response to targeted and chemo therapies when multiple targets are proposed.

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          Most cited references32

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          Personalized In Vitro and In Vivo Cancer Models to Guide Precision Medicine.

          Precision medicine is an approach that takes into account the influence of individuals' genes, environment, and lifestyle exposures to tailor interventions. Here, we describe the development of a robust precision cancer care platform that integrates whole-exome sequencing with a living biobank that enables high-throughput drug screens on patient-derived tumor organoids. To date, 56 tumor-derived organoid cultures and 19 patient-derived xenograft (PDX) models have been established from the 769 patients enrolled in an Institutional Review Board-approved clinical trial. Because genomics alone was insufficient to identify therapeutic options for the majority of patients with advanced disease, we used high-throughput drug screening to discover effective treatment strategies. Analysis of tumor-derived cells from four cases, two uterine malignancies and two colon cancers, identified effective drugs and drug combinations that were subsequently validated using 3-D cultures and PDX models. This platform thereby promotes the discovery of novel therapeutic approaches that can be assessed in clinical trials and provides personalized therapeutic options for individual patients where standard clinical options have been exhausted.Significance: Integration of genomic data with drug screening from personalized in vitro and in vivo cancer models guides precision cancer care and fuels next-generation research. Cancer Discov; 7(5); 462-77. ©2017 AACR.See related commentary by Picco and Garnett, p. 456This article is highlighted in the In This Issue feature, p. 443.
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            Interrogating open issues in cancer precision medicine with patient-derived xenografts

            This Opinion article discusses progress and challenges in using patient-derived xenograft (PDX) models in cancer precision medicine. It is primarily co-authored by members of the EurOPDX Consortium and as such highlights the merits of shared PDX resources.
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              Affinity of human IgG subclasses to mouse Fc gamma receptors.

              Human IgG is the main antibody class used in antibody therapies because of its efficacy and longer half-life, which are completely or partly due to FcγR-mediated functions of the molecules. Preclinical testing in mouse models are frequently performed using human IgG, but no detailed information on binding of human IgG to mouse FcγRs is available. The orthologous mouse and human FcγRs share roughly 60-70% identity, suggesting some incompatibility. Here, we report binding affinities of all mouse and human IgG subclasses to mouse FcγR. Human IgGs bound to mouse FcγR with remarkably similar binding strengths as we know from binding to human orthologue receptors, with relative affinities IgG3>IgG1>IgG4>IgG2 and FcγRI>FcγRIV>FcγRIII>FcγRIIb. This suggests human IgG subclasses to have similar relative FcγR-mediated biological activities in mice.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                22 January 2019
                2019
                : 9
                : 17
                Affiliations
                [1] 1The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev , Beer Sheva, Israel
                [2] 2National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev , Beer Sheva, Israel
                [3] 3Department of Otolaryngology-Head and Neck Surgery, Soroka Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev , Beer Sheva, Israel
                [4] 4Department of Otolaryngology-Head and Neck Surgery and The Center for Translational Research in Head and Neck Cancer, Rabin Medical Center, Petah Tikva and Sackler Faculty of Medicine, Tel Aviv University , Tel Aviv, Israel
                [5] 5Worldwide Innovative Network Association-WIN Consortium , Villejuif, France
                Author notes

                Edited by: Giovanna Schiavoni, Istituto Superiore di Sanità (ISS), Italy

                Reviewed by: Natalie Julie Serkova, University of Colorado, United States; Silviya Petrova Zustiak, Saint Louis University, United States

                *Correspondence: Moshe Elkabets moshee@ 123456bgu.ac.il

                This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Oncology

                †These authors have contributed equally to this work

                ‡These authors have contributed equally to this work

                Article
                10.3389/fonc.2019.00017
                6350270
                30723707
                8a1f756e-7167-4988-b93a-a907bf35bb86
                Copyright © 2019 Ghosh, Prasad, Kundu, Cohen, Yegodayev, Zorea, Joshua, Lasry, Dimitstein, Bahat-Dinur, Mizrachi, Lazar, Elkabets and Porgador.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 18 October 2018
                : 07 January 2019
                Page count
                Figures: 5, Tables: 1, Equations: 2, References: 42, Pages: 12, Words: 7757
                Categories
                Oncology
                Original Research

                Oncology & Radiotherapy
                head and neck cancer,patient derived xenografts,ex vivo,explant culture,targeted therapy

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