Two Houston Methodist cancer researchers have been awarded a half million dollars in funding from the Cancer Prevention and Research Institute of Texas (CPRIT) to further research two of the most lethal, difficult-to-treat cancers that all-too-often have poor prognoses.

Jenny C. Chang, M.D., director of Houston Methodist Dr. Mary and Ron Neal Cancer Center and Emily Hermann Chair in Cancer Research, received a $250,000 grant to study the interaction between obesity and nitric oxide synthase (NOS) in triple-negative breast cancer (TNBC).

Chang says TNBC, already the worst prognosis among the subtypes of breast cancer, has even worse outcomes in obese patients. These patients have a higher chance of resisting chemo and an increased risk of relapse and poorer survival. She says the reason is unclear, but evidence indicates it's associated with chronic inflammation and that two essential players of chronic inflammation – tumor neutrophil infiltration and nitric oxide (NO) levels – have been identified to play pivotal roles in obesity-associated TNBC.

Studies have shown that obesity reprograms the tumor microenvironment and that this reprograming is accompanied by increased nitric oxide levels that, along with infiltrating neutrophils, compromise vascular integrity and cause increased breast cancer metastasis. Chang and her team propose that NOS inhibition will reverse the immunosuppressive tumor microenvironment to enhance the efficacy of the current standard of care. 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, as well as help the design of successful clinical trials to enhance the appropriate selection of TNBC patients who would benefit from chemotherapy and/or immune checkpoint therapy.

Jing Yang, Ph.D., an associate professor of oncology with the Houston Methodist Research Institute and member of the Houston Methodist Neal Cancer Center, received a $250,000 grant to study multiple myeloma, which is the second most common blood cancer, to improve the therapeutic efficacy and survival in these patients. Specifically, Yang and her team are looking at a novel FDA-approved monoclonal antibody treatment, daratumumab (DARA), that has shown to improve therapeutic efficacy when combined with other drugs, but falls short in patients with high-risk multiple myeloma who too often relapse or don't respond to the treatment at all.

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Yang's team believe they found a clue to better understand how multiple myeloma cells resist DARA and keep it from being effective. Using the largest public database for multiple myeloma patients, they examined tumor gene expression and patients' best clinical response, which led them to identifying a protein called NHE6 that may be involved in multiple myeloma's resistance to treatment with DARA. They found that the NHE6 protein is highly expressed in multiple myeloma cells, and its high expression is correlated with patients' poorer prognoses, high-risk genetic features and multiple myeloma stage progression. Ultimately, these multiple myeloma cells with the high NHE6 level were less responsive to DARA.

Yang and team's plan is to investigate the role and mechanism by which NHE6 induces DARA resistance and develop NHE6 as a new target to improve DARA efficacy in murine models and patients. The knowledge gained from their study should uncover innovative insight into how multiple myeloma cells escape from DARA treatment. Given that DARA is an emerging compound used as standard care for multiple myeloma patients, they believe their new strategy of targeting NHE6 and developing an inhibitor to do so could significantly improve DARA-based multiple myeloma therapy outcomes.