A potential therapeutic target for triple negative breast cancer (TNBC) has been pinpointed by researchers at Virginian Commonwealth University (VCU) Massey Cancer Center. Importantly, this target may be effective in black patients, who suffer disproportionally from the disease. Further, the researchers may have a lead on a biomarker—c-MYC—to guide treatment.
Massey scientists, led by Anthony Faber, PhD, and Jennifer Koblinski, PhD, used CRISPR/CAS9 screening to zero in on an enzyme called UBA1. Using a novel UBA-inhibiting drug called TAK-243, they blocked the cellular function of UBA1 and effectively killed cancer cells in patient-derived breast tumors in mice. The study was published in PNAS Nexus.
Previous research has shown that UBA1 inhibitors can have a positive impact in hematological cancers such as acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML). This study is the first to suggest that UBA1 inhibitors could be effective in TNBC. TAK-243 has been tested recently in early phase trials, paving the way for potential testing in TNBC patients.
These researchers also determined that the c-MYC gene—an important drug target in TNBC—can be harnessed to enable TAK-243 to initiate a cellular stress response and enhance the drug’s ability to fight TNBC. This supports the notion that TAK-243 may be effective in high-cMYC-expressing TNBC, where c-MYC may serve as a biomarker for response to the drug.
The hormone receptors, estrogen receptors or human epidermal growth factor receptor 2 (HER2) that can be effectively targeted in breast cancer treatment are missing in TNBC, hence the name “triple-negative breast cancer.”
“We found that the majority of TNBC cells in our study were uniformly susceptible to the antitumor effects of TAK-243,” said Koblinski, director of the Cancer Mouse Models Core and member of the Cancer Biology research program at Massey, as well as an associate professor of pathology at the VCU School of Medicine. “In addition to demonstrating this drug’s success at the local site of the primary breast cancer, our findings demonstrate that TAK-243 can also shrink tumors in various organs after the disease has spread.”
Breast cancer is the second most common cancer in U.S. women, and triple-negative breast cancer (TNBC) is a more aggressive and deadly form of disease that accounts for approximately 12% of all breast tumors. TNBC grows and spreads more quickly than other breast tumors and is associated with worse patient outcomes, accounting for nearly one-third of all breast cancer-related deaths. Chemotherapy remains one of the few routinely utilized treatment options for TNBC, with variable patient responses and little efficacy.
Additionally, Black women die from TNBC at a significantly higher rate than white women despite being diagnosed at a younger age. Finding an effective therapy that works well in all patients would be an important step in addressing this disparity.
“The implementation of targeted therapies—drugs that target a specific genetic defect— has been revolutionary in treating different cancers, including breast cancer,” said Faber, co-leader of the Developmental Therapeutics research program.
“Genomic and clinical evidence suggests that the implementation of targeted therapies in the treatment of TNBC will require an expansion of potential targets,” Faber said. “Our study may have identified a key and novel target for the development of new therapies.”
Faber added, “The most exciting part of the study was that we found TAK-243 was effective across these models [including mouse models using cells from black patients], suggesting TAK-243 or other UBA1 inhibitors could be equally effective in all TNBC patients.”
The next steps of this research, the team says, will include exploring the use of TAK-243 in TNBC, and evaluating other targets in the UBA1 pathway that may also demonstrate efficacy.
