High Fidelity Patient-Derived Xenografts for Accelerating Prostate Cancer Discovery and Drug Development
Top Cited Papers
Open Access
- 15 February 2014
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 74 (4), 1272-1283
- https://doi.org/10.1158/0008-5472.can-13-2921-t
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. Cancer Res; 74(4); 1272–83. ©2013 AACR.Keywords
Other Versions
This publication has 52 references indexed in Scilit:
- Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 studyThe Lancet Oncology, 2012
- Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancerNature Genetics, 2012
- The mutational landscape of lethal castration-resistant prostate cancerNature, 2012
- From sequence to molecular pathology, and a mechanism driving the neuroendocrine phenotype in prostate cancerThe Journal of Pathology, 2012
- ERG–TMPRSS2 rearrangement is shared by concurrent prostatic adenocarcinoma and prostatic small cell carcinoma and absent in small cell carcinoma of the urinary bladder: evidence supporting monoclonal originLaboratory Investigation, 2011
- ERG gene rearrangements are common in prostatic small cell carcinomasLaboratory Investigation, 2011
- The genomic complexity of primary human prostate cancerNature, 2011
- Integrative Genomic Profiling of Human Prostate CancerCancer Cell, 2010
- Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostateNature Genetics, 2009
- Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancerNature Medicine, 2009