Targeting the Prostate Cancer Microenvironment to Improve Therapeutic Outcomes.

摘要

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 mTOR/NF-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.