Novel Therapeutic Targets to Inhibit Tumor Microenvironment-Induced Castration-Resistant Prostate Cancer.

摘要

We previously demonstrated that stromal TGF-beta signaling induced the expression of several AR targets as well as MAPK4 in PCa LNCaP cells, and that MAPK4 induced ligand-independent AR activation in PCa cells. Therefore, we proposed to use in vitro PCa/stroma co-culture models and in vivo xenograft models to test our hypothesis on stromal TGF-beta signaling inducing MAPK4 for androgen-independent AR activation in PCa as a direct mechanism for CRPC relapse. In this first year, we have demonstrated that stromal TGF-beta signaling induces AR activation, and that this AR activation is largely independent of androgen ligand. These data strongly supports our hypothesis. We have published a research paper describing this part of study. We have also generated several key reagents to support our proposed in vitro and in vivo studies in the second and third years. We expect to be able to finish all the proposed studies at the conclusion of this award.