Scientists identify targeted drug target in aggressive breast cancer — ScienceDaily

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

Breast cancer is the second most common cancer in women in the US, 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.

Additionally, TNBC disproportionately affects black women: black women die from TNBC at significantly higher rates 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 discrepancy.

Through a comprehensive and cutting-edge 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, which turned out 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 patient-derived breast tumors in mice.

Previous research has shown that UBA1 inhibitors may have a positive impact in hematological cancers such as acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML). This study – recently published in PNAS Nexus — was the first to suggest that UBA1 inhibitors might be effective in TNBC. TAK-243 was recently tested in early phase trials, 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, as well as an associate professor in pathology at the VCU School of Medicine. “In addition to demonstrating the success of this drug at the local site of primary breast cancer, our findings show that TAK-243 can also shrink tumors in various organs after the disease has spread.”

The researchers also found that the c-MYC gene—an important and notoriously difficult drug target in TNBC—could be used to cooperate with TAK-243 to initiate a cellular stress response and improve the drug’s ability to fight with TNBC. This supports the idea that TAK-243 may be effective in highly cMYC-expressing TNBC, where c-MYC may serve as a biomarker of drug response.

Chemotherapy remains one of the few routinely used treatment options for TNBC, with variable patient responses and little efficacy.

“The application of targeted therapies — drugs that target a specific genetic defect — has been revolutionary in the treatment of various types of cancer, including breast cancer,” said Faber, co-director of the Developmental Therapeutics Research Program and the Natalie N. and John R. Congdon, Sr., Massey Endowed Chair in Cancer Research, as well as Associate Professor at the Philips Institute for Oral Health Research at the VCU School of Dental Medicine.

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

“Genomic and clinical evidence suggests that the implementation of targeted therapies in the treatment of TNBC will require expanding the potential targets,” said Faber. “Our study may have identified a key and novel target for the development of new therapies.”

Faber added, “Importantly, because TNBC is a major disease with disparate outcomes between black patients 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 the group of Mr. Koblinski. 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 these models, suggesting that TAK-243 or other UBA1 inhibitors may be equally effective in all TNBC patients.”

The next steps of this research 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.

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Materials provided by Virginia Commonwealth University. Original written by Blake Belden. Note: Content may be edited for style and length.

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