A co-clinical approach identifies mechanisms and potential therapies for androgen deprivation resistance in prostate cancer

Nat Genet. 2013 Jul;45(7):747-55. doi: 10.1038/ng.2650. Epub 2013 Jun 2.

Abstract

Here we report an integrated analysis that leverages data from treatment of genetic mouse models of prostate cancer along with clinical data from patients to elucidate new mechanisms of castration resistance. We show that castration counteracts tumor progression in a Pten loss-driven mouse model of prostate cancer through the induction of apoptosis and proliferation block. Conversely, this response is bypassed with deletion of either Trp53 or Zbtb7a together with Pten, leading to the development of castration-resistant prostate cancer (CRPC). Mechanistically, the integrated acquisition of data from mouse models and patients identifies the expression patterns of XAF1, XIAP and SRD5A1 as a predictive and actionable signature for CRPC. Notably, we show that combined inhibition of XIAP, SRD5A1 and AR pathways overcomes castration resistance. Thus, our co-clinical approach facilitates the stratification of patients and the development of tailored and innovative therapeutic treatments.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgen Antagonists / therapeutic use*
  • Androgens / metabolism*
  • Animals
  • Antineoplastic Agents / therapeutic use
  • Cell Line, Tumor
  • Drug Evaluation, Preclinical
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Models, Biological
  • Orchiectomy
  • PTEN Phosphohydrolase / genetics
  • Phenylthiohydantoin / analogs & derivatives
  • Phenylthiohydantoin / therapeutic use
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms / therapy*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Therapies, Investigational*
  • Translational Medical Research / methods
  • Treatment Failure

Substances

  • Androgen Antagonists
  • Androgens
  • Antineoplastic Agents
  • MDV 3100
  • Phenylthiohydantoin
  • PTEN Phosphohydrolase
  • Pten protein, mouse