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 XuRavi Amaravadi, Tara C. Gangadhar, David E. Elder, Lauren E. Haydu, Jennifer A. Wargo, Michael A. Davies, Yiling Lu, Gordon 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

Research output: Contribution to journalArticle

37 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1953-1967
Number of pages15
JournalCell Reports
Volume21
Issue number7
DOIs
StatePublished - Nov 14 2017
Externally publishedYes

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Keywords

  • BRAF inhibitor resistance
  • ERK inhibitor
  • immune checkpoint blockade
  • in vivo models
  • MDM2 inhibitor
  • melanoma
  • melanoma brain metastasis
  • patient-derived xenografts
  • PI3K beta inhibitor
  • targeted therapy

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Krepler, C., Sproesser, K., Brafford, P., Beqiri, M., Garman, B., Xiao, M., Shannan, B., Watters, A., Perego, M., Zhang, G., Vultur, A., Yin, X., Liu, Q., Anastopoulos, I. N., Wubbenhorst, B., Wilson, M. A., Xu, W., Karakousis, G., Feldman, M., ... Herlyn, M. (2017). A Comprehensive Patient-Derived Xenograft Collection Representing the Heterogeneity of Melanoma. Cell Reports, 21(7), 1953-1967. https://doi.org/10.1016/j.celrep.2017.10.021