Scr as a Therapeutic Target in Prostate Cancer Bone Metastases

Instnjctions):

Instnjctions): Current strategies for PCa treatment that target primarily the primary tumor or preserve bone have only modestly affected survival. The focus of this laboratory and collaborators for many years has been on Src family kinases (SFKs), the activation of which not only contribute to PCa metastasis in mouse models, by affecfing tumor cells, osteoclasts, osteoblasts and interacfions between these cells required for tumor cell growth in the bone. This project will test the central hypothesis that therapeutic strategies using Src inhibitors currently in clinical trial will prove efficacious in the treatment of PCa metastases in the bone. The rafionale for this hypothesis is that Src regulates signaling pathways both in tumor cells and in their microenvironment that contribute to the "vicious cycle" of bone formafion, degradation and tumor growth, and is based, in part, on the promise of an ongoing phase l/ll clinical trial for metastafic prostate cancer using the combinafion of dasafinib (an SFK/AbI inhibitor) and docetaxel. This project will combine mechanistic-based strategies in preclinical mouse model systems to examine the specific contributions of Src in the host and tumor cell contribufing to growth in the bone with a phase III clinical trial using dasafinib. The specific aims are to: (1) Determine the role of SFK inhibition in tumor cells, host cells, and both in affecting growth of PCa cells following intrafibial injecfion into nude mice; (2) Determine molecular alterafions in the tumor and host correlating with the effectiveness of dasatinib; and (3) Integrate this knowledge with a phase III trial using dasatinib in combinafion with docetaxel in a phase III trial in select pafients with castrate resistant prostate cancer and bone metastases, correlate changes in molecular markers of Src and bone preservation with clinical course of the disease. The trial will serve as a platform to associate markers of Src activation, with baseline and serial change(s) in bone turnover markers. Thus, the experiments in Project 3 are novel in that they build on a promising therapeutic strategy, which we also view as reiterative, where our increased knowledge of Src's effects in tumor/bone interacfion will help dictate clinical trial design, and the clinical trials will help refine modeling the disease in preclinical studies. RELEVANCE (See instnjctions): Currently, no successful therapies exist for the treatment of late-stage prostate cancer (i.e. cancer that has metastasized, especially to the bone). However recent early-stage clinical trials using inhibitors of Src, which affects both tumor growth and interaction of tumor with its environment, have been promising. In this project, we will employ basic science strategies to understand which Src functions are crifical to this process, and use this knowledge in a phase III clinical trial to design better treatments for prostate cancer.