Cell Reports (Nov 2017)
A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma
- Clemens Krepler,
- Katrin Sproesser,
- Patricia Brafford,
- Marilda Beqiri,
- Bradley Garman,
- Min Xiao,
- Batool Shannan,
- Andrea Watters,
- Michela Perego,
- Gao Zhang,
- Adina Vultur,
- Xiangfan Yin,
- Qin Liu,
- Ioannis N. Anastopoulos,
- Bradley Wubbenhorst,
- Melissa A. Wilson,
- Wei Xu,
- Giorgos Karakousis,
- Michael Feldman,
- Xiaowei Xu,
- Ravi Amaravadi,
- Tara C. Gangadhar,
- David E. Elder,
- Lauren E. Haydu,
- Jennifer A. Wargo,
- Michael A. Davies,
- Yiling Lu,
- Gordon B. Mills,
- Dennie T. Frederick,
- Michal Barzily-Rokni,
- Keith T. Flaherty,
- Dave S. Hoon,
- Michael Guarino,
- Joseph J. Bennett,
- Randall W. Ryan,
- Nicholas J. Petrelli,
- Carol L. Shields,
- Mizue Terai,
- Takami Sato,
- Andrew E. Aplin,
- Alexander Roesch,
- David Darr,
- Steve Angus,
- Rakesh Kumar,
- Ensar Halilovic,
- Giordano Caponigro,
- Sebastien Jeay,
- Jens Wuerthner,
- Annette Walter,
- Matthias Ocker,
- Matthew B. Boxer,
- Lynn Schuchter,
- Katherine L. Nathanson,
- Meenhard Herlyn
Affiliations
- Clemens Krepler
- Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, PA 19104, USA
- Katrin Sproesser
- Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, PA 19104, USA
- Patricia Brafford
- Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, PA 19104, USA
- Marilda Beqiri
- Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, PA 19104, USA
- Bradley Garman
- Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Min Xiao
- Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, PA 19104, USA
- Batool Shannan
- Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, PA 19104, USA
- Andrea Watters
- Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, PA 19104, USA
- Michela Perego
- Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, PA 19104, USA
- Gao Zhang
- Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, PA 19104, USA
- Adina Vultur
- Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, PA 19104, USA
- Xiangfan Yin
- Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, PA 19104, USA
- Qin Liu
- Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, PA 19104, USA
- Ioannis N. Anastopoulos
- Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Bradley Wubbenhorst
- Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Melissa A. Wilson
- Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Wei Xu
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Giorgos Karakousis
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Michael Feldman
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Xiaowei Xu
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Ravi Amaravadi
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Tara C. Gangadhar
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- David E. Elder
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Lauren E. Haydu
- MD Anderson Cancer Center, University of Texas, Houston, TX 77030, USA
- Jennifer A. Wargo
- MD Anderson Cancer Center, University of Texas, Houston, TX 77030, USA
- Michael A. Davies
- MD Anderson Cancer Center, University of Texas, Houston, TX 77030, USA
- Yiling Lu
- MD Anderson Cancer Center, University of Texas, Houston, TX 77030, USA
- Gordon B. Mills
- MD Anderson Cancer Center, University of Texas, Houston, TX 77030, USA
- Dennie T. Frederick
- Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA
- Michal Barzily-Rokni
- Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA
- Keith T. Flaherty
- Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA
- Dave S. Hoon
- Translational Molecular Medicine, John Wayne Cancer Institute, Santa Monica, CA 90404, USA
- Michael Guarino
- Helen F. Graham Cancer Center at Christiana Care, Newark, DE 19713, USA
- Joseph J. Bennett
- Helen F. Graham Cancer Center at Christiana Care, Newark, DE 19713, USA
- Randall W. Ryan
- Helen F. Graham Cancer Center at Christiana Care, Newark, DE 19713, USA
- Nicholas J. Petrelli
- Helen F. Graham Cancer Center at Christiana Care, Newark, DE 19713, USA
- Carol L. Shields
- Ocular Oncology Service, Wills Eye Hospital, Philadelphia, PA 19107, USA
- Mizue Terai
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107
- Takami Sato
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107
- Andrew E. Aplin
- Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107
- Alexander Roesch
- Department of Dermatology, University Duisburg-Essen, University Hospital Essen, 45147 Essen, Germany; German Consortium of Translational Cancer Research, Heidelberg, Germany
- David Darr
- Lineberger Cancer Center, University of North Carolina Chapel Hill, NC 27514, USA
- Steve Angus
- Lineberger Cancer Center, University of North Carolina Chapel Hill, NC 27514, USA
- Rakesh Kumar
- Glaxosmithkline, Collegeville, PA 19426, USA
- Ensar Halilovic
- Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA
- Giordano Caponigro
- Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA
- Sebastien Jeay
- Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA
- Jens Wuerthner
- Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA
- Annette Walter
- Bayer Pharma AG, Berlin 13353, Germany
- Matthias Ocker
- Bayer Pharma AG, Berlin 13353, Germany
- Matthew B. Boxer
- National Center for Advancing Translational Sciences, NIH, Rockville, MD 20850, USA
- Lynn Schuchter
- Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Katherine L. Nathanson
- Department of Medicine, Division of Translational Medicine and Human Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Meenhard Herlyn
- Molecular and Cellular Oncogenesis Program, Wistar Institute, Philadelphia, PA 19104, USA; Corresponding author
- Journal volume & issue
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Vol. 21,
no. 7
pp. 1953 – 1967
Abstract
Summary: 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: melanoma, patient-derived xenografts, targeted therapy, immune checkpoint blockade, melanoma brain metastasis, in vivo models, BRAF inhibitor resistance, ERK inhibitor, MDM2 inhibitor, PI3K beta inhibitor
