Scientists pinpoint drug target for aggressive breast cancer

Researchers at the VCU Massey Cancer Center have targeted a new therapeutic target for an aggressive form of breast cancer with limited treatment options.

Breast cancer is the second most common cancer in American women and triple negative breast cancer (TNBC) is a more aggressive and deadly form of the disease, accounting for 10-15% of all breast tumors.

TNBC grows and spreads faster than other breast tumors and is associated with worse patient outcomes, accounting for nearly one-third of all breast cancer-related deaths.

In addition, TNBC disproportionately affects black women: black women are significantly more likely to die from TNBC 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.

Using a comprehensive and advanced genomic screening method known as CRISPR/CAS9 screening, Massey scientists led by Anthony Faber, Ph.D., and Jennifer Koblinski, Ph.D., were able to identify a specific enzyme called UBA1 that proved to be an ideal therapeutic target. Using a new UBA-inhibiting drug called TAK-243, they blocked the cellular function of UBA1 and effectively killed cancer cells in breast tumors in mice.

Previous studies have shown that UBA1 inhibitors may have a positive effect on hematological cancers such as acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). This study, recently published in PNAS Nexus— is the first to suggest that UBA1 inhibitors may be effective in TNBC. TAK-243 was recently tested in an early phase trial, paving the way for potential testing in TNBC patients.

“We found that the majority of TNBC cells in our study were equally 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, and associate professor of pathology at the VCU School of Medicine. “In addition to demonstrating the success of this drug in the local setting of primary breast cancer, our findings demonstrate that TAK-243 can also shrink tumors in various organs after the disease has spread.”

The researchers also determined that the c-MYC gene—an important and notoriously difficult drug target in TNBC—could be used to interact with 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 TNBC with high cMYC expression, where c-MYC may serve as a biomarker for drug response.

Chemotherapy remains one of the few commonly used treatment options for TNBC, with variable patient response and poor efficacy.

“The introduction of targeted therapy — drugs that target a specific genetic defect — has revolutionized the treatment of many cancers, including breast cancer,” said Faber, co-director of the Developmental Therapeutics Research Program and the Natalie N. and John R. Congdon, Senior Chair of Cancer Research at Massey and Associate Professor of the Philips Oral Health Research Institute at the VCU School of Dentistry.

However, Art hormonal receptorsEstrogen receptors or human epidermal growth factor receptor 2 (HER2), which can be effectively targeted in breast cancer treatment, are absent in TNBC, hence the name “triple negative breast cancer.”

“Genomic and clinical data suggest that the implementation of targeted therapy in the treatment of TNBC will require an expansion of potential targets,” said Faber. “Our study may have identified a key and novel target for the development of new treatments.”

He added: “Importantly, because TNBC is a major disease with disparate outcomes between black and white patients, we were able to harness the power of new mouse models of breast cancer from black TNBC patients that were developed by Dr. Koblinski’s group. Traditionally, these models have been underrepresented and are important new tools for identifying effective therapies for black patients. The most exciting part of the study was that we found that TAK-243 was effective in all of these models, suggesting that TAK-243 or other UBA1 inhibitors may be equally effective in all TNBC patients.”

The next steps in this study include exploring the use of TAK-243 in TNBC with the pharmaceutical company developing it and evaluating other targets in the UBA1 pathway that may also demonstrate efficacy.