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Updated: Feb 8, 2026

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
07:25

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer

Published on: March 6, 2018

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Neoadjuvant-Intensive Androgen Deprivation Therapy Selects for Prostate Tumor Foci with Diverse Subclonal Oncogenic

Adam G Sowalsky1,2, Huihui Ye3, Manoj Bhasin4

  • 1Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.

Cancer Research
|June 21, 2018
PubMed

Insights

Primary prostate cancer harbors aggressive subclones that are selected by neoadjuvant androgen deprivation therapy. These subclones, particularly those with RB1 loss, may drive the development of metastatic castration-resistant prostate cancer.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Prostate cancer exhibits microheterogeneity, but its role in metastatic castration-resistant prostate cancer (mCRPC) development is not fully understood.
  • Neoadjuvant androgen deprivation therapy (ADT) is a common treatment for prostate cancer, but its impact on subclonal evolution requires further investigation.

Purpose of the Study:

  • To investigate the contribution of primary prostate cancer microheterogeneity to the emergence of mCRPC.
  • To identify resistance mechanisms selected by neoadjuvant-intensive ADT in residual prostate cancer foci.

Main Methods:

  • Microdissection of residual prostate cancer foci from radical prostatectomies of 18 patients treated with neoadjuvant ADT (leuprolide, abiraterone acetate, prednisone).
  • Transcriptome profiling to assess AR activity and neuroendocrine differentiation.
  • Whole-exome sequencing (WES) to identify genomic alterations, including RB1 loss and subclonal evolution.

Main Results:

  • Residual tumors showed reduced but persistent androgen receptor (AR) activity without increased neuroendocrine differentiation.
  • RB1 expression correlated negatively with proliferation, and WES revealed enrichment for RB1 genomic loss.
  • WES confirmed common clonal origins but identified unique oncogenic alterations in distinct tumor foci, indicating subclonal heterogeneity.

Conclusions:

  • Subclones with oncogenic alterations characteristic of mCRPC are present in primary prostate cancer and are selected by neoadjuvant ADT.
  • Subclonal RB1 loss may be an early, frequent event in intermediate- to high-risk prostate cancer, preceding neuroendocrine differentiation and contributing to mCRPC.
  • Comprehensive molecular analysis of primary tumors could identify aggressive subclones and guide adjuvant therapy strategies to prevent recurrence.

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