Grant to Pursue Triple-Negative Breast Cancer Targeted Therapy Awarded to Ohio State

The U.S. Department of Defense has awarded a three-year, $1.17 million grant to help researchers at the OSUCCC – James develop a cell-surface molecule called RAGE as a biomarker and therapeutic target for triple-negative breast cancer (TNBC).

Principal investigator for the study is Ramesh Ganju, PhD, a professor in the Department of Pathology at Ohio State. Ganju, who also is a member of the Molecular Biology and Cancer Genetics Program at the OSUCCC – James, notes that TNBC has the poorest prognosis and worst survival rates of all breast cancers due to early metastasis to other organs and a lack of clinically established targeted therapies.

In their project abstract, Ganju and co-investigators Bhuvaneswari Ramaswamy, MD, of the Translational Therapeutics Program at the OSUCCC – James, and Dinesh Ahirwar, PhD, a research scientist in the Department of Pathology at Ohio State, describe RAGE (receptor for advanced glycation end products) as a member of the immunoglobulin superfamily of cell surface molecules that has been associated with chronic inflammation. The researchers, who have shown that RAGE is expressed in a panel of aggressive breast cancer cell lines, TNBC and metastatic patient samples, want to learn more about its mechanisms so they can develop targeted therapies that may be effective for patients with TNBC.

TNBC is so named because it is negative for the three biomarkers typically used to determine breast cancer treatment: the estrogen receptor, the progesterone receptor, and HER2/neu. Patients are said to have TNBC when their tumors do not express these receptors.

“Very limited information is available about the mechanisms through which RAGE enhances breast cancer growth and metastasis,” Ganju’s team states in their abstract. They add that further mechanistic studies are necessary, especially those exploring its role in modulating the tumor microenvironment and oncogenic signaling pathways.

Based on prior observation, the team hypothesizes that RAGE expressed by epithelial cells cross-talks with the EGFR gene to enhance oncogenic signaling. They also hypothesize that RAGE expressed on myeloid cells/macrophages suppresses immune responses by enhancing tumor-associated macrophage (TAM) recruitment. Given these hypotheses, they believe RAGE could be used as a biomarker and therapeutic target for TNBC and other metastatic breast cancers.

Their study has three aims: 1) analyze RAGE-mediated oncogenic signaling in tumor cells that enhance metastasis; 2) investigate the role of RAGE in modulating the activities of myeloid cells/macrophages in stroma (the area surrounding the tumor); and 3) examine the clinical significance of RAGE in TNBC.

“This study will elucidate novel RAGE-mediated mechanisms, especially its cross-talk with EGFR that enhances oncogenic signaling to promote metastasis,” they write. “The study also will define the role of RAGE in modulating the tumor microenvironment that leads to metastatic niche formation.” In addition, they will “develop RAGE as a biomarker and determine if it could be used as a therapeutic target, especially for TNBC patients.”

Since TNBC patients currently are treated with chemotherapy and lack specific therapeutic targets, the scientists conclude that this study could have “overarching significance” in developing treatments and improving prognosis.