Accession Number:

ADA626552

Title:

Targeting the Prostate Cancer Microenvironment to Improve Therapeutic Outcomes

Descriptive Note:

Final rept. 15 May 2012-15 May 2015

Corporate Author:

SEATTLE INST FOR BIOMEDICAL AND CLINICAL RESEARCH SEATTLE WA

Personal Author(s):

Report Date:

2015-08-01

Pagination or Media Count:

42.0

Abstract:

Therapies designed to damage DNA e.g. chemotherapy and irradiation cure many primary prostate carcinomas PCa and produce significant responses in a subset of advanced malignancies. However, a subset of localized cancers resist genotoxic treatments, and most advanced cancers treated with such therapies eventually progress to a lethal phenotype. Thus, therapy resistance is a major contributor to PCa morbidity and mortality. We want to explore the hypothesis that DNA damaging therapeutics generates responses in benign cell types comprising the tumor microenvironment TME that promote tumor cell survival and enhance resistance. We have assessed the outcome of targeting individual mediators of this microenvironment-derived DDSP---specifically a member of the Wnt superfamily, WNT16B and demonstrated the highly effective neutralization of PCa cell malignancy in vitro by purified anti-WNT16B. We have established primary mouse prostate fibroblast cell lines and examined their responses including DDSP development upon DNA damage, and demonstrated the potential complication of regulatory mechanisms of DDSP program. Further, we determined the functional roles of the master regulators of DDSP including mTORNF-kB, and found the physical interaction between these molecules when cells are exposed to genotoxicity. We anticipate that targeting such a key signaling network is able to diminish treatment-initiated resistance conferred by the TME, and promote in vivo tumor responses in clinical settings of PCa medicine.

Subject Categories:

  • Anatomy and Physiology
  • Medicine and Medical Research
  • Toxicology

Distribution Statement:

APPROVED FOR PUBLIC RELEASE