# Normalizing arginine metabolism with sepiaptein for immunostimulatory-shift of HER2+ breast cancer

> **NIH NIH R01** · UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS · 2021 · $353,419

## Abstract

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 f...

## Key facts

- **NIH application ID:** 10119271
- **Project number:** 5R01CA248304-02
- **Recipient organization:** UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
- **Principal Investigator:** Saori Furuta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $353,419
- **Award type:** 5
- **Project period:** 2020-03-04 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10119271

## Citation

> US National Institutes of Health, RePORTER application 10119271, Normalizing arginine metabolism with sepiaptein for immunostimulatory-shift of HER2+ breast cancer (5R01CA248304-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10119271. Licensed CC0.

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