Development of metastasis in bone is the lethal progression of prostate cancer (PCa). Most approved therapeutic agents only modestly improve patient survival. PCa bone metastasis is unique in that the bone lesions tend to be bone forming rather than bone lysing, which occurs in other cancers. PCa-induced aberrant bone supports cancer cells’ survival and resistance to chemotherapy. Thus, traditional cancer therapy that targets tumor cells has failed to impact patients’ survival. Our proposed studies will target the tumor-induced aberrant bone formation as an integral part of treatment for bone metastasis. Our studies on the mechanism of PCa-induced aberrant bone formation revealed a surpri...

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Development of metastasis in bone is the lethal progression of prostate cancer (PCa). Most approved therapeutic agents only modestly improve patient survival. PCa bone metastasis is unique in that the bone lesions tend to be bone forming rather than bone lysing, which occurs in other cancers. PCa-induced aberrant bone supports cancer cells’ survival and resistance to chemotherapy. Thus, traditional cancer therapy that targets tumor cells has failed to impact patients’ survival. Our proposed studies will target the tumor-induced aberrant bone formation as an integral part of treatment for bone metastasis. Our studies on the mechanism of PCa-induced aberrant bone formation revealed a surprising bone-forming role of endothelial cells in PCa bone metastasis. Identification of this unique mechanism leads us to discover that PCa-induced aberrant bone formation shares a striking similarity with a genetic disease fibrodysplasia ossificans progressiva (FOP), also known as stoneman disease. We linked these two seemingly unrelated diseases based on their disease mechanisms. Such a connection leads us to consider repurposing a promising FOP therapeutic agent, palovarotene, currently in phase 3 clinical trial for FOP, for the treatment of PCa bone metastasis. We hypothesize that RAR-gamma agonists, including palovarotene, can be used to inhibit aberrant bone formation in PCa bone metastasis. The combination of RAR-gamma agonists with current therapies will enhance therapy outcomes for bone metastasis. Our objectives are to examine whether palovarotene and other RAR-gamma agonists will inhibit PCa-induced aberrant bone formation and block prostate tumor growth in bone. Palovarotene is being tested as a long-term control of a genetic disease and its toxicity is low, making its combination with other cancer-targeted therapies possible and promising. We expect that this novel therapy will have significant impact on patients’ survival.

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