The major challenge in the treatment of patients with advanced lethal
prostate cancer is therapeutic resistance to
androgen-deprivation
therapy (ADT) and
chemotherapy. Overriding this resistance requires understanding of the driving mechanisms of the tumor microenvironment, not just the
androgen receptor (AR)-signaling cascade, that facilitate therapeutic resistance in order to identify new drug targets. The tumor microenvironment enables key signaling pathways promoting
cancer cell survival and invasion via resistance to anoikis. In particular, the process of epithelial-mesenchymal-transition (EMT), directed by
transforming growth factor-β (TGF-β), confers stem cell properties and acquisition of a migratory and invasive phenotype via resistance to anoikis. Our lead agent DZ-50 may have a potentially high efficacy in advanced metastatic
castration resistant
prostate cancer (mCRPC) by eliciting an anoikis-driven therapeutic response. The plasticity of differentiated prostate
tumor gland epithelium allows cells to de-differentiate into mesenchymal cells via EMT and re-differentiate via reversal to mesenchymal epithelial transition (MET) during
tumor progression. A characteristic feature of EMT landscape is loss of
E-cadherin, causing adherens junction breakdown, which circumvents anoikis, promoting
metastasis and chemoresistance. The targetable interactions between
androgens/AR and TGF-β signaling are being pursued towards optimized therapeutic regimens for the treatment of mCRPC. In this review, we discuss the recent evidence on targeting the EMT-MET dynamic interconversions to overcome therapeutic resistance in patients with recurrent therapeutically resistant
prostate cancer. Exploitation of the phenotypic landscape and metabolic changes that characterize the prostate tumor microenvironment in advanced
prostate cancer and consequential impact in conferring treatment resistance are also considered in the context of
biomarker discovery.