Grant: Operating Grant

Deaths from prostate cancer (PCa) are the consequence of "castration-resistant" disease (CRPC) that grows and spreads despite the use of hormone therapy. Research now shows that a factor leading to CRPC is the acquisition of androgen synthetic capability by the tumor as this allows it to replace androgens lost due to hormone therapy. Our recent work indicates that Paracrine Hedgehog signaling activity, awakened by hormone therapy, can be a factor that enables prostate tumors to make their own androgens. Hedgehogs are small proteins that activate Hedgehog signaling in target cells and, for a prostate tumor, the preferred targets are the benign stromal cells that surround the tumor. Previously we showed that hormone therapy drastically increases the synthesis and release of Hedgehogs from PCa cells. New studies show that Hedgehog action on prostate stromal cells promotes the synthesis and release of testosterone from these cells. Collectively, our studies then suggest that a complex cross-talk process between PCa cells and surrounding stromal cells (referred to as Paracrine activity) supports the development of CRPC. The goals of this project will be to explain the reason that hormone therapy increases Hedgehog release from PCa cells and to characterize the process(es) through which Paracrine Hedgehog enables production of androgens from prostate stromal cells as a means of considering ways to block it. Likewise, we will test new strategies involving combinations of Hedgehog gene knockdown, Hedgehog inhibitors and steroid biosynthesis inhibitors for prevention of CRPC and for treatment of CRPC in our cell models. Finally, we will establish a practical animal model based on implantation of mixtures of human prostate cells under the outer capsule of the mouse kidney to establish the relevance of Paracrine Hedgehog in PCa development and progression and to test our combination treatment strategies to fight CRPC before they are tested in patients