Towards identifying genetic determinants of radioresistant prostate cancer

Authors

  • S Kartal
  • SY Trostel
  • RT Lis
  • AG Sowalsky
  • DE Citrin

Abstract

Background: Radiotherapy (RT) is commonly used for treating localized prostate cancer (PCa). For high-risk organ-confined PCa, androgen deprivation therapy (ADT) is often given with definitive RT. ADT enhances RT by affecting androgen receptor (AR) transcriptional activity and interfering with AR-mediated DNA double-strand break repair. We aim to investigate the genetic and phenotypic changes associated with resistance to RT ± ADT by comparing pretreatment and time of recurrence benign epithelial cells, tumor cells and stroma.

Methods: Tissue samples were collected before treatment and at the time of clinical or biochemical recurrence in a prospective study of patients with intermediate or high-risk PCa treated with RT ± ADT. 30 patients have paired pre-treatment and post-treatment biopsies (templated, US/MRI-fusion targeted). H&E-stained slides were scanned and annotated. Immunostains, including PTEN, ERG, and PIN-4 cocktail, were applied. Laser capture microdissection (LCM) was used to capture regions for whole-transcriptome and whole exome sequencing.

Results and conclusions:
Annotation is complete for 27 matched pairs of patient samples. LCM has been completed in two cases with matched pre- and post-treatment tissues. We will provide an update on the patterns of gene expression and genomic analyses of these tissues. Our analysis will include differentially enriched pathways in radiated stroma and benign glands relative to the corresponding pre-treatment tissue. Differentially enriched pathways in recurrent will be compared to baseline tumor samples to identify potential mechanisms of radiorecurrence regarding genetic changes will aid in the identification of pre-existing resistance tumor clones and opportunities for precision systemic therapy.

Scientific Focus Area: Clinical Research

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