Predicting Drug Response in Human Prostate Cancer From Preclinical Analysis of In Vivo Mouse Models

Cell Rep. 2015 Sep 29;12(12):2060-71. doi: 10.1016/j.celrep.2015.08.051. Epub 2015 Sep 17.

Abstract

Although genetically engineered mouse (GEM) models are often used to evaluate cancer therapies, extrapolation of such preclinical data to human cancer can be challenging. Here, we introduce an approach that uses drug perturbation data from GEM models to predict drug efficacy in human cancer. Network-based analysis of expression profiles from in vivo treatment of GEM models identified drugs and drug combinations that inhibit the activity of FOXM1 and CENPF, which are master regulators of prostate cancer malignancy. Validation of mouse and human prostate cancer models confirmed the specificity and synergy of a predicted drug combination to abrogate FOXM1/CENPF activity and inhibit tumorigenicity. Network-based analysis of treatment signatures from GEM models identified treatment-responsive genes in human prostate cancer that are potential biomarkers of patient response. More generally, this approach allows systematic identification of drugs that inhibit tumor dependencies, thereby improving the utility of GEM models for prioritizing drugs for clinical evaluation.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Biomarkers, Pharmacological / metabolism
  • Carcinogenesis / drug effects
  • Carcinogenesis / genetics
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology
  • Cell Line, Tumor
  • Chromosomal Proteins, Non-Histone / antagonists & inhibitors*
  • Chromosomal Proteins, Non-Histone / genetics
  • Chromosomal Proteins, Non-Histone / metabolism
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Drug Synergism
  • Forkhead Box Protein M1
  • Forkhead Transcription Factors / antagonists & inhibitors*
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Microfilament Proteins / antagonists & inhibitors*
  • Microfilament Proteins / genetics
  • Microfilament Proteins / metabolism
  • Predictive Value of Tests
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / mortality
  • Prostatic Neoplasms / pathology
  • Signal Transduction
  • Survival Analysis

Substances

  • Antineoplastic Agents
  • Biomarkers, Pharmacological
  • Chromosomal Proteins, Non-Histone
  • Forkhead Box Protein M1
  • Forkhead Transcription Factors
  • Foxm1 protein, mouse
  • Microfilament Proteins
  • centromere protein F

Associated data

  • GEO/GSE69211
  • GEO/GSE69213