Obesity is a major health concern and contributes to various diseases including breast cancer. Triple-negative breast cancer (TNBC) is an aggressive and highly lethal subtype of breast cancer. Obese TNBC patients often have the worse outcome with a higher chance of resistance to traditional chemotherapy and increased risk of tumor recurrence. While the mechanism responsible for this outcome is unknown, evidence indicates its association with chronic inflammation. One of the inflammatory pathways being studied by our group is the nitric oxide synthases (NOS) pathway. We and others have shown that increased nitric oxide levels alter the tumor immune cell profile that lead to increased breast c...

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Obesity is a major health concern and contributes to various diseases including breast cancer. Triple-negative breast cancer (TNBC) is an aggressive and highly lethal subtype of breast cancer. Obese TNBC patients often have the worse outcome with a higher chance of resistance to traditional chemotherapy and increased risk of tumor recurrence. While the mechanism responsible for this outcome is unknown, evidence indicates its association with chronic inflammation. One of the inflammatory pathways being studied by our group is the nitric oxide synthases (NOS) pathway. We and others have shown that increased nitric oxide levels alter the tumor immune cell profile that lead to increased breast cancer metastasis. Furthermore, in a recently completed Phase I/II clinical trial, we found that inhibition of the NOS pathway by the pan-NOS inhibitor NG-methyl-L-arginine acetate (L-NMMA), increased the response rate to chemotherapy in obese metastatic TNBC patients to 86% vs. 60% in normal-weight TNBC patients. We, therefore, propose that NOS inhibition will reverse the immunosuppressive tumor environment to enhance the efficacy of standard of care chemotherapy and/or novel immune-checkpoint inhibitors such as anti-programmed death-1 (PD-1) antibodies. To accomplish this, mice fed with either regular or high-fat diets will be randomized into control, single therapy, and combo (docetaxel plus L-NMMA and anti-PD1) groups. We will evaluate tumor progression and metastasis in these mice, and comprehensive analysis of immunological changes in both tumor and blood during treatment will be measured. Successful completion of the 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 and help design of successful clinical trials to enhance the appropriate selection of TNBC patients that would benefit from chemotherapy and/or immune checkpoint therapy.

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