title: High fidelity patient-derived xenografts for accelerating prostate cancer discovery and drug development.
abstract: Standardized and reproducible preclinical models that recapitulate the dynamics of prostate cancer are urgently needed. We established a bank of transplantable patient-derived prostate cancer xenografts that capture the biologic and molecular heterogeneity currently confounding prognostication and therapy development. Xenografts preserved the histopathology, genome architecture, and global gene expression of donor tumors. Moreover, their aggressiveness matched patient observations, and their response to androgen withdrawal correlated with tumor subtype. The panel includes the first xenografts generated from needle biopsy tissue obtained at diagnosis. This advance was exploited to generate independent xenografts from different sites of a primary site, enabling functional dissection of tumor heterogeneity. Prolonged exposure of adenocarcinoma xenografts to androgen withdrawal led to castration-resistant prostate cancer, including the first-in-field model of complete transdifferentiation into lethal neuroendocrine prostate cancer. Further analysis of this model supports the hypothesis that neuroendocrine prostate cancer can evolve directly from adenocarcinoma via an adaptive response and yielded a set of genes potentially involved in neuroendocrine transdifferentiation. We predict that these next-generation models will be transformative for advancing mechanistic understanding of disease progression, response to therapy, and personalized oncology.
authors.affiliation: Authors' Affiliations: Vancouver Prostate Centre; Department of Urologic Sciences, Faculty of Medicine, University of British Columbia; Departments of Experimental Therapeutics and Radiation Oncology, BC Cancer Agency, Vancouver, British Columbia, Canada; Departments of Medicine and Pathology and Laboratory Medicine, Weill Cornell Cancer Center, Weill Cornell Medical College, New York, New York.
authors.forename: Dong
authors.initials: D
authors.lastname: Lin
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Wyatt
authors.forename: Hui
authors.initials: H
authors.lastname: Xue
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Wang
authors.forename: Xin
authors.initials: X
authors.lastname: Dong
authors.forename: Anne
authors.initials: A
authors.lastname: Haegert
authors.forename: Rebecca
authors.initials: R
authors.lastname: Wu
authors.forename: Sonal
authors.initials: S
authors.lastname: Brahmbhatt
authors.forename: Fan
authors.initials: F
authors.lastname: Mo
authors.forename: Lina
authors.initials: L
authors.lastname: Jong
authors.forename: Robert H
authors.initials: RH
authors.lastname: Bell
authors.forename: Shawn
authors.initials: S
authors.lastname: Anderson
authors.forename: Antonio
authors.initials: A
authors.lastname: Hurtado-Coll
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.forename: Manju
authors.initials: M
authors.lastname: Sharma
authors.forename: Himisha
authors.initials: H
authors.lastname: Beltran
authors.forename: Mark
authors.initials: M
authors.lastname: Rubin
authors.forename: Michael
authors.initials: M
authors.lastname: Cox
authors.forename: Peter W
authors.initials: PW
authors.lastname: Gout
authors.forename: James
authors.initials: J
authors.lastname: Morris
authors.forename: Larry
authors.initials: L
authors.lastname: Goldenberg
authors.forename: Stanislav V
authors.initials: SV
authors.lastname: Volik
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.forename: Colin C
authors.initials: CC
authors.lastname: Collins
authors.forename: Yuzhuo
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis* / Q000188:drug therapy*; D000818:Animals; D000970:Antineoplastic Agents / Q000302:isolation & purification*; D045744:Cell Line, Tumor; D055808:Drug Discovery / Q000379:methods*; D055088:Early Detection of Cancer / Q000379:methods*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation / Q000592:standards; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000188:drug therapy*; D009927:Tissue and Organ Procurement / Q000592:standards; D023041:Xenograft Model Antitumor Assays / Q000592:standards
chemical_list: D000970:Antineoplastic Agents