Weill Cornell Medicine has received a $2.5 million, three-year grant from the Department of Defense (DoD) to develop therapies with fewer side effects for triple-negative breast cancer, one of the most aggressive and difficult-to-treat breast cancers. The highly competitive DoD Breast Cancer Research Program Breakthrough Award supports innovative projects with strong potential to transform breast cancer treatment.
Triple-negative breast cancer lacks three proteins—estrogen receptor, progesterone receptor and HER2—that many of today's targeted therapies attack, leaving many patients limited to chemotherapy as their primary treatment option.
Dr. Xiaojing Ma
"Patients with triple-negative breast cancer urgently need better treatment options," said co-principal investigator Dr. Xiaojing Ma, professor of microbiology and immunology, and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell. “We believe the UBR5 protein is an entirely new vulnerability in these tumors, and this award provides an opportunity to translate years of basic discovery into therapies that could ultimately benefit patients."
Dr. Ma is working with Dr. Gang Lin, professor of research in microbiology and immunology at Weill Cornell and co-principal investigator, to develop first-in-class drugs targeting UBR5, which is frequently overproduced in aggressive breast cancers and several other difficult-to-treat malignancies. Unlike most existing therapies, targeting UBR5 has the potential to simultaneously interfere with multiple cancer-promoting mechanisms.
In healthy cells, UBR5 helps regulate the activity and turnover of many proteins involved in cell growth, DNA repair and tagging damaged or faulty proteins for disposal. However, Dr. Ma and his team previously discovered that many cancers hijack UBR5 to promote tumor growth, spread and resistance to immune attack.
In a highly cited 2017 paper, Dr. Ma’s lab showed that genetically disrupting the UBR5 gene in preclinical models slowed breast tumor growth and reduced the ability of cancer cells to metastasize to other organs. The findings provided the first compelling evidence that UBR5 is not merely associated with breast cancer but is functionally required for tumor growth and metastasis, motivating the team's effort to develop drugs that target the protein.
Dr. Gang Lin
Dr. Ma partnered with Dr. Lin, a medicinal chemist well-versed in developing drugs that interfere with the actions of specific proteins. In addition to designing small molecule drugs that block UBR5, the researchers will develop protein degraders, an emerging type of medicine that directs the cell's own waste-disposal system to destroy harmful proteins. Because many tumors produce substantially higher levels of UBR5 than most normal tissues, the researchers anticipate these therapies will selectively target cancer cells while reducing side effects.
Their labs have uncovered several compounds that inhibit UBR5 at high concentrations, providing the proof-of-concept needed to launch the current project.
“The potency is not ideal yet; achieving an effective dose on-target requires high concentrations that may induce side effects,” Dr. Lin said. “This grant will help us tweak the structures of the inhibitors to make them effective at much lower concentrations.”
The team will then evaluate how well the drugs work against breast cancer in laboratory models that closely mimic human cancers. “A big win will be optimizing these drug candidates and generating the data needed to move into the next phase of development,” Dr. Lin said.
“Although the current project focuses on triple-negative breast cancer, UBR5 is also overproduced in ovarian, pancreatic and prostate cancers,” Dr. Ma said. “Success in this program could open the door to a new generation of targeted therapies for multiple aggressive cancers.”
