@article{c9e64dc345954b788e8dcb807b2ae8ce,
title = "A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma",
abstract = "Therapy of advanced melanoma is changing dramatically. Following mutational and biological subclassification of this heterogeneous cancer, several targeted and immune therapies were approved and increased survival significantly. To facilitate further advancements through pre-clinical in vivo modeling, we have established 459 patient-derived xenografts (PDX) and live tissue samples from 384 patients representing the full spectrum of clinical, therapeutic, mutational, and biological heterogeneity of melanoma. PDX have been characterized using targeted sequencing and protein arrays and are clinically annotated. This exhaustive live tissue resource includes PDX from 57 samples resistant to targeted therapy, 61 samples from responders and non-responders to immune checkpoint blockade, and 31 samples from brain metastasis. Uveal, mucosal, and acral subtypes are represented as well. We show examples of pre-clinical trials that highlight how the PDX collection can be used to develop and optimize precision therapies, biomarkers of response, and the targeting of rare genetic subgroups. Krepler et al. have established a collection of melanoma patient-derived xenografts (PDX). Melanoma is a very heterogeneous cancer, and this large collection includes even rare subtypes and genetic aberrations in sufficient numbers. Multiple PDX from therapy-resistant patients are characterized and tested in pre-clinical trials for second line therapies.",
keywords = "BRAF inhibitor resistance, ERK inhibitor, MDM2 inhibitor, PI3K beta inhibitor, immune checkpoint blockade, in vivo models, melanoma, melanoma brain metastasis, patient-derived xenografts, targeted therapy",
author = "Clemens Krepler and Katrin Sproesser and Patricia Brafford and Marilda Beqiri and Bradley Garman and Min Xiao and Batool Shannan and Andrea Watters and Michela Perego and Gao Zhang and Adina Vultur and Xiangfan Yin and Qin Liu and Anastopoulos, {Ioannis N.} and Bradley Wubbenhorst and Wilson, {Melissa A.} and Wei Xu and Giorgos Karakousis and Michael Feldman and Xiaowei Xu and Ravi Amaravadi and Gangadhar, {Tara C.} and Elder, {David E.} and Haydu, {Lauren E.} and Wargo, {Jennifer A.} and Davies, {Michael A.} and Yiling Lu and Mills, {Gordon B.} and Frederick, {Dennie T.} and Michal Barzily-Rokni and Flaherty, {Keith T.} and Hoon, {Dave S.} and Michael Guarino and Bennett, {Joseph J.} and Ryan, {Randall W.} and Petrelli, {Nicholas J.} and Shields, {Carol L.} and Mizue Terai and Takami Sato and Aplin, {Andrew E.} and Alexander Roesch and David Darr and Steve Angus and Rakesh Kumar and Ensar Halilovic and Giordano Caponigro and Sebastien Jeay and Jens Wuerthner and Annette Walter and Matthias Ocker and Boxer, {Matthew B.} and Lynn Schuchter and Nathanson, {Katherine L.} and Meenhard Herlyn",
note = "Funding Information: We thank the animal, genomics, histology, flow cytometry, and imaging core facilities at the Wistar Institute. We thank the Perelman School of Medicine Biobank, University of Pennsylvania (Federico Valdivieso, Caitlin Feltcher, Amber McKeown, and Emma Gasper) with support from the Perelman School of Medicine and Abramson Cancer Center ( P30 CA016520-40 ). We thank Lori E. Huelsenbeck-Dill and Patricia L. Swanson at the Helen F. Graham Cancer Center. We thank the tissue collection core facilities at the MD Anderson Cancer Center, Massachusetts General Hospital, and John Wayne Cancer Institute. We thank Drew A. Torigian for CT image analysis. We thank G. Bollag at Plexxikon for supplying PLX4720. Support for the shared resources utilized in this study was provided by a Cancer Center Support Grant (CCSG) ( P30CA010815 ) to the Wistar Institute, a Cancer Center Support Grant (CCSG) ( CA016672 ) to MDACC, and the MDACC Melanoma SPORE ( P50 CA093459 ). This work was supported by NIH grants ( P01 CA114046 , P01 CA025874 , and R01 CA047159 to M.H.; R01 CA182635 to A.E.A.; R01 CA198015 and 5P30 CA016520 to R.A.); a SPORE grant on Skin Cancer to the Wistar Institute and the University of Pennsylvania ( P50 CA174523-02 ); the Margaretta and R.R.M Carpenter Foundation ; the SR Cancer Stem Cell Research Program (to the Helen F. Graham Cancer Center at Christiana Care); the University of North Carolina Cancer Research Fund (to D.D.); philanthropic contributions to The University of Texas MD Anderson Cancer Center Melanoma Moon Shot Program; and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation . The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was supported in part by grants from GSK , Novartis , and Bayer . Publisher Copyright: {\textcopyright} 2017 The Authors",
year = "2017",
month = nov,
day = "14",
doi = "10.1016/j.celrep.2017.10.021",
language = "English (US)",
volume = "21",
pages = "1953--1967",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "7",
}