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

Abstract : 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 second year, we have met some technical problems including altered expression of MAPK4 in the continuously cultured LNCaP cells with stable overexpression or knockdown of MAPK4. Accordingly, we have generated LNCaP cells with Dox-inducible knockdown or Doxinducible overexpression of MAPK4. We have also created HPS19I cells overexpressing the dominant negative TbetaRII. These provide key reagents for our proposed in vitro and in vivo studies. We expect to be able to finish the proposed studies at the conclusion of this award.