Normalizing arginine metabolism with sepiaptein for immunostimulatory-shift ofHER2+ breast cancer

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In cancer cells and the tumor microenvironment, arginine metabolism is often shunted into the pathways that produce polyamines, small polycationic metabolites essential for cell growth and immuno-suppression. Such mechanisms in part account for the refractoriness of certain types of cancers, including breast cancer, to immunotherapy. However, there is a critical gap in developing a method to correct arginine metabolism to improve the immunogenicity of breast cancer. The long-term goal of our project is to develop an adjuvant treatment to improve breast cancer immunotherapy with little side effects. Specifically, the objective of this study is to test whether sepiapterin, the naturally-occurring precursor of nitric oxide synthase (NOS) cofactor BH4, could normalize arginine metabolism in the breast to prevent cancer formation or enhance the efficacy of breast cancer immunotherapy. Our central hypothesis is that sepiapterin shunts arginine metabolism into the pathways for NO synthesis in breast cancer cells and tumor-associated macrophages (TAMs). Such shifts reduce polyamine production, suppress tumor growth and immuno-suppressive mechanisms. This improves the efficacy of cancer immunotherapy with little systemic toxicity. Our hypothesis is based on the results of our and others’ previous studies. The two major arginine metabolic pathways, NO production vs. polyamine synthesis, antagonize each other. Consistently, we found that sepiapterin elevates NO synthesis and inhibits growth-stimulatory and immune-suppressive molecules, such as polyamines, while converting TAMs from M2 (immuno-suppressive) to M1 (immuno-stimulatory) types within tumors. Besides, sepiapterin has been safely utilized in humans and animals to treat certain metabolic disorders. The rationale is that this study will help develop a novel method to normalize arginine metabolism and improve the immunogenicity of breast cancer. Our hypothesis will be tested through two SPECIFIC AIMS: 1) Determine whether sepiapterin normalizes arginine metabolism in mammary tumor cells and tumor microenvironment Determine the efficacy and safety of sepiapterin for the treatment and prevention of HER2-positive mammary tumor. In Aim 1, breast cancer cells, TAMs and mammary tumors are treated with sepiapterin in culture, and their metabolites and the respective enzymes are measured. In Aim 2, mice bearing or prone to HER2-positive mammary tumors are treated with sepiapterin and tested for the inhibition or prevention of tumor growth. The proposed study is innovative because it tests for the first time whether sepiapterin, the naturally produced precursor of the NOS ; and 2) cofactor, could normalize arginine metabolism, improve the immunogenicity of breast cancer to inhibit the growth or prevent breast cancer formation. The study is significant because it will have a positive translational impact by justifying the use of sepiapterin as an adjuvant to breast cancer immunotherapy or a preventative agent for breast cancer. Given that there is currently no FDA-approved immunotherapy for HER2-positive breast cancer, successful results of this study will warrant future clinical trials.