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42005scr b46d4c398585d1cby Hannah Buckelew

Selvarangan Ponnazhagan, Ph.D., Endowed Professor in Experimental Cancer Therapeutics in the UAB Department of Pathology’s Division of Molecular and Cellular Pathology, has recently been awarded a $1.7 million R01 grant from the National Cancer Institute based on his project submission, titled, “Mechanisms and therapeutic targeting of osteoimmune functions of RANKL in breast cancer.” The award will run through March 31, 2027.

Current treatments for patients with breast cancer bone metastases have shown that targeting tumor cells alone is not sufficient for long-term survival, but a multi-faceted approach is needed to inhibit tumor cells in the bone microenvironment that drive immunosuppression and tumor growth. As breast cancer spreads throughout the bone, tumor cells interact with reactive stroma. This results in the production of cytokines and other small proteins necessary for cell signaling that activate the expression of nuclear factor kappa-B ligand (RANKL), and cause aggressive bone damage.

“We want to expand our understanding of the roles of RANKL in immune suppression and bone damage,” Ponnazhagan says. “We will test the potential of a combination therapy to reverse tumor-associated pathology in the immune and skeletal systems.”

The first part of the team’s study will elucidate the role and mechanisms of upregulated RANKL in tumor cells. Next, they will work toward developing a biologically-driven systemic therapy for pre-metastatic and metastatic breast cancer, targeting the protumorigenic osteoimmune functions of elevated RANKL.

“We’re proposing a genetically engineered cell therapy, expressing an osteoprotegerin (OPG) variant we developed by structure-based protein engineering,” Ponnazhagan says. “We found that its application in pre-metastatic disease significantly decreases metastasis of breast cancer in vivo.”

Ponnazhagan’s team will employ immunocompetent mouse models to determine the role of RANKL both in protumorigenic myeloid cell function and non-canonical signaling on PD-L1 expression during breast cancer bone metastasis and interpret the therapeutic effects of the OPG variant by additionally dampening PD-L1 levels. The OPG variant cell therapy will be tested with a programmed cell death protein 1 antibody and chemotherapy in pre-metastatic and metastatic breast cancer.

Co-investigators on this study include Gene Siegal, M.D. Ph.D., and Xu Feng Ph.D., in the UAB Department of Pathology, Jessy Deshane, Ph.D., in UAB's Division of Pulmonary, Allergy and Critical Care Medicine and Erica Stringer-Reasor, M.D., in UAB's Division of Hematology and Oncology. 

“The knowledge from this study will assist in developing a biologically driven combination therapy that addresses immune suppression, tumor growth, and skeletal-related events to extend the life expectancy of patients, especially those with pre-metastatic high-risk breast cancer,” Ponnazhagan says.