Daratumumab Resistance in Multiple Myeloma May Be Associated With High Levels of NHE6 Expression

Two Houston Methodist cancer researchers were granted a quarter of a million dollars each to study some of the most lethal cancers.

With a focus on finding more effective treatments for difficult-to-treat cancers that are often fatal, the Cancer Prevention and Research Institute of Texas (CPRIT) recently awarded cancer researchers Jenny C. Chang, MD, and Jing Yang, PhD, a combined total of $500,000. Chang, the director of Houston Methodist Dr. Mary and Ron Neal Cancer Center and Emily Hermann Chair in Cancer, received a $250,000 grant to study the links between nitric oxide synthase (NOS) and obesity in triple-negative breast cancer (TNBC), while Yang, an associate professor of oncology at the Houston Methodist Research Institute and member of the Houston Methodist Neal Cancer Center, received $250,000 to study multiple myeloma and find more effective treatments to improve survival.

Out of all of the breast cancer subtypes, TNBC has some of the worst treatment outcomes, explained Chang in the press release. TNBC has been observed to be more resistant to chemotherapy and patients with the disease have an increased risk of relapse and death. Patients who are obese also are even more likely to suffer from worse outcomes due to TNBC.

“Successful completion of their proposed work will provide an improved understanding of the role of the NOS inhibitors in TNBC and may define prognostic markers in obese TNBC patients at a higher risk of mortality,” wrote the press release authors.

Previous research found that obesity can also play a role in reprogramming of the tumor microenvironment. This reprogramming can result in greater nitric oxide (NO) levels, which Chang explained are associated with chronic inflammation. Tumor neutrophil infiltration is also associated with chronic inflammation, which may increase the metastasis of TNBC—possibly leading to worse outcomes among patients who are obese.

Chang and team suggest that inhibiting NOS may enhance the efficacy of current TNBC standard of care. Knowledge of NOS inhibitors in TNBC might also enhance the appropriate selection of TNBC patients who would benefit from chemotherapy and/or immune checkpoint therapy, the press release authors explained.

For Yang and team, they will look at daratumumab (DARA) in the treatment of multiple myeloma, which is one of the most common blood cancers. Yang said that DARA, although an FDA-approved monoclonal antibody treatment that has been shown to be effective as a combination treatment, is not always successful for high-risk multiple myeloma patients.

Specifically, Yang and team found that patients who express the NHE6 protein at elevated rates may be less responsive to DARA. To investigate this further, Yang and team will study DARA resistance that occurs from high levels of NHE6 expression to improve DARA efficacy. Further, Yara noted that the investigation team predicts that targeting NHE6 and developing an inhibitor to do so could significantly improve DARA-based multiple myeloma therapy outcomes.

“The knowledge gained from their study should uncover innovative insight into how multiple myeloma cells escape from DARA treatment,” the authors of the press release wrote.

Reference

Houston Methodist. Taking aim at triple-negative breast cancer and multiple myeloma to improve prognoses. EurekAlert! September 27, 2022. Accessed on September 27, 2022. https://www.eurekalert.org/news-releases/966030