Prostate cancer (PCa) is dominated by complications arising from bone metastasis, which often has a lethal outcome. Currently, immunotherapeutic approach for prostate cancer is limited because PCa bone metastasis is resistant to immune checkpoint therapy. This study aims to develop a novel combination therapeutic approach to revitalize immunotherapy in bone metastatic prostate cancer. PCa bone metastasis is unique in that the bone lesions tend to be bone forming rather than bone lysing, which occurs in other cancers. Our studies established that PCa-induced aberrant bone formation recruits immunosuppressive myeloid cells that leads to resistance to immune checkpoint therapy. Our propos...

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Prostate cancer (PCa) is dominated by complications arising from bone metastasis, which often has a lethal outcome. Currently, immunotherapeutic approach for prostate cancer is limited because PCa bone metastasis is resistant to immune checkpoint therapy. This study aims to develop a novel combination therapeutic approach to revitalize immunotherapy in bone metastatic prostate cancer. PCa bone metastasis is unique in that the bone lesions tend to be bone forming rather than bone lysing, which occurs in other cancers. Our studies established that PCa-induced aberrant bone formation recruits immunosuppressive myeloid cells that leads to resistance to immune checkpoint therapy. Our proposed studies will target the tumor-induced aberrant bone formation as an integral part of immune checkpoint 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 palovarotene in combination with current immune checkpoint therapy will enhance therapy outcomes for bone metastasis. Palovarotene is being tested as a long-term control of genetic disease FOP and its toxicity is low, making its combination with other cancer-targeted therapies possible and promising. We expect that this novel therapy combination will improve the quality of life and prolong the survival of patients with bone metastasis.

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