$2.5M DoD grant supports targeted therapy development for triple-negative breast cancer

Weill Cornell Medicine has secured a $2.5 million, three-year Department of Defense (DoD) Breakthrough Award to create new therapies for triple-negative breast cancer, a subtype widely known for its aggressive behavior and limited treatment options. The program is designed to accelerate innovative approaches with real potential to change patient care.

Triple-negative breast cancer is defined by the absence of three common targets: estrogen receptor, progesterone receptor, and HER2. Because standard targeted therapies depend on these proteins, many patients ultimately rely on chemotherapy, which can be burdensome and less effective over time.

The project is led by co-principal investigator Dr. Xiaojing Ma, whose team focuses on an underappreciated vulnerability in these tumors: the UBR5 protein. Dr. Ma and colleagues argue that UBR5 is not just correlated with cancer, but can be functionally required for tumor growth and metastatic spread.

UBR5 normally helps cells manage protein life cycles, including regulating protein abundance and facilitating the removal of damaged or faulty proteins. In cancer, however, UBR5 can be hijacked to support multiple tumor-promoting processes, including mechanisms that help tumors resist immune attack.

In preclinical work published in 2017, Dr. Ma’s lab showed that disrupting the UBR5 gene in model systems slowed breast tumor growth and reduced metastasis. This finding provided the rationale for developing direct therapies aimed at UBR5.

The DoD-funded effort pairs Dr. Ma with medicinal chemist Dr. Gang Lin to engineer first-in-class drug strategies targeting UBR5. Beyond small-molecule inhibitors, the team will also pursue protein degraders, therapies that leverage the cell’s own quality-control machinery to eliminate disease-driving proteins.

Although the group has identified compounds that suppress UBR5 activity at high concentrations, achieving therapeutic effectiveness at lower doses remains a key challenge. The grant will support structure optimization to improve potency while minimizing the risk of side effects.

A central goal is to test candidate drugs in laboratory models that better reflect human disease biology. Success would not only advance triple-negative breast cancer therapy, but could also extend to other malignancies where UBR5 is frequently overproduced, including ovarian, pancreatic, and prostate cancers.