Regenerative Stem Cell Therapy for Breast Cancer Bone Metastasis

Abstract : Bone is the most common site of metastasis for human breast cancer (BCa), which results in significant morbidity and mortality in patients with advanced disease. A vicious cycle, arising due to the interaction of BCa cells and cells in the bone microenvironment results in the activation of osteoclasts and increased osteolytic bone destruction. The major treatment to reduce the burden of bone metastasis in BCa patients is bisphosphonate therapy. Despite significant efforts to improve the potency of bisphosphonates, the complications are only retarded but not prevented. Thus, development of newer therapies that can both ameliorate the threshold of bone destruction and increase survival of patients with metastatic breast disease will be highly beneficial. The central hypothesis of the proposed work is bone-targeted delivery of genetically-engineered MSC, over-expressing OPG, will prevent osteolytic bone damage and restore skeletal remodeling. Further, based on the requirement of angiogenesis for tumor growth in primary and metastatic sites, in combination with a systemically stable anti-angiogenic therapy, long-term survival will significantly increase. These hypotheses will be tested in this proposal using an immnocompetent, preclinical mouse model of BCa dissemination to all major bones as in human patients.