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Dr._Ponns.pngSelvarangan Ponnazhagan, Ph.D., Professor, Molecular and Cellular Pathology, received a $80,000 research grant from UAB's O'Neal Comprehensive Cancer Center using funds provided by the Breast Cancer Research Foundation of Alabama (BCRFA) to fund his research proposal titled, "Combinatorial genetic immunotherapy and RANKL antagonism for breast cancer." 

Immunotherapy is a promising avenue for treating metastatic breast cancer. Yet, translation of successful strategies from animal studies to the clinic has so far produced only modest anti-tumor responses in patients. From these clinical trials, however, several limitations have become apparent that need to be overcome. The principle of cancer immunotherapy is to activate a patient’s own immune system to recognize and kill tumor cells. However, as the tumor grows, it secretes chemicals around, which block the immune cells from attacking them. We have identified that in addition to tumor cells, immune cells and bone corroding cells called osteoclasts in the tumor environment also respond to tumor secreted chemicals and adapt themselves to helping the growing tumor thereby contributing to the vicious cycle of immune suppression and bone damage.

Effective therapies to cure metastatic breast cancer should simultaneously address these pathologies. Toward this ultimate goal, Dr. Ponnazhagan proposes to test unique combination therapies that are biologically-driven and have shown promise in preliminary studies. He will adopt a genetic antibody engineering approach to establish a stable therapeutic strategy to overcome current limitations in breast cancer immunotherapy. This novel approach will follow a protocol of a one-time application for long-lasting therapeutic benefit as opposed to current therapies that need repeat infusions, yet prove ineffective. Results of preliminary studies provided in this proposal offer great optimism, superiority, and promise for validating the studies. Since the combination therapies proposed are based on biological molecules and not synthetic drugs, they are not only safe, but also exhibit sustained effects in the body, which is critical to achieving long-term therapy gains without disease resistance that is normally encountered with chemotherapy.

Dr. Ponnazhagan's research has two specific aims: to determine the potential of a combination immunotherapy using anti-PD-L1 scFv and MDSC depletion for primary and metastatic BCa in vivo, and to determine the therapeutic effects of combinatorial genetic PD-L1 blockade and RANKL antagonism in overcoming immunosuppression and skeletal pathology in BCa in vivo. A positive outcome of these studies will provide opportunities to test new, biologically-driven therapeutic options for BCa. 

Strategies proposed in the grant application are expected to simultaneously overcome the disease burden from compounding defective immune system and bone damage. Successful completion of the studies in a preclinical model of metastatic breast cancer that mimics the characteristics of the disease in human patients will enable Dr. Ponnazhagan to develop an R01 grant application for the National Cancer Institute, to bring the significance of a novel combination therapy for metastatic breast cancer one step closer to being a reality.