Pilot Testing of VEGF/PDGF inhibitors for chemoprevention of bone metastasis

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DESCRIPTION (provided by applicant): A vast majority of prostate cancer patients die with metastases and almost 90% of prostate cancer metastases occur at skeletal sites. It is thought that prostate carcinoma-initiated bone remodeling is a critical early event for tumor cell colonization to the bone, since the normal adult bone matrix is not conducive to tumor colonization. Once prostate cancer cells metastasize to bone, there is no effective therapy to offer a survival advantage. Importantly, recent clinical studies showed that docetaxel-based chemotherapy improves median survival by nearly two months in patients with advanced hormone-refractory prostate cancer, opening up the possibility of chemoprevention of prostate cancer progression in bone. Prostate cancer is a slow- growing, heterogeneous tumor that requires multimodality therapy. It becomes clear that therapy should target not only tumor growth but also tumor-mediated stromal responses. Studies suggest that platelet- derived growth factor receptor-beta (beta-PDGFR) signaling promotes prostate bone metastasis via its regulation of osteoprogenitor cell migration, proliferation and differentiation. Our recent study has revealed that prostate tumor-produced PDGF D, a newly discovered ligand for beta-PDGFR, drastically enhances tumor-take and growth rate in the bone environment and mediates both osteolytic and osteoblastic responses, possibly leading to net growth of bone. The objectives of this R03 application are (Aim 1) to validate the use of our animal model engineered to upregulate PDGF D/ beta-PDGFR signaling for screening of PDGF/VEGF inhibitors and test the efficacy of PDGF/VEGF inhibitors, AZD2171 and Gleevec, combined with docetaxel for chemoprevention of prostate cancer progression in bone, and (Aim 2) to investigate the effects of AZD2171 and Gleevec on tumor-derived PDGF D-induced signal transduction and gene expression in bone stromal cells in vitro. Considering that beta-PDGFR is highly upregulated in both bone metastases and primary prostate cancer specimens, the completion of the proposed study will provide important information with therapeutic value of PDGF targeting. Theses studies will also validate our animal model engineered to upregulate beta-PDGFR signaling for screening of PDGF/VEGF inhibitors in the future. This information will be useful in designing more rational therapeutic interventions aimed at modulating the PDGF/VEGF signaling pathways.