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Principal Investigator: Saori Furuta
Organization: CASE WESTERN RESERVE UNIVERSITY
Fiscal Year: 2024
Award: $349,874
Funding agency: National Cancer Institute
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.
Terms: <2-amino-6-(S)-lactoyl-7,8-dihydro-4(3H)- pteridinone><Adjuvant><Adjuvant Therapy><Aminoacetic Acid><Animals><Arginine><Arginine decarboxylase><Argininosuccinase><Argininosuccinate Synthetase><B7-H1><B7H1><BH4><BPH4><Breast><Breast Cancer><Breast Cancer Cell><Breast Cancer Prevention><Breast Neoplasms><Breast Tissue><Breast Tumors><CD274><Cancers><Cellular Expansion><Cellular Growth><Clinical Trials><Drug resistance><EDRF Synthase><ERBB2><ERBB2 gene><Endothelium-Derived Growth Factor Synthase><Enzyme Gene><Enzymes><FDA approved><Future><Generalized Growth><Glycine><Goals><Growth><Guanylyl Cyclase-Activating Factor Synthase><H4B><H4biopterin><HER -2><HER-2><HER2><HER2 Genes><HER2/neu><Hepatic Proliferation Inhibitor><Human><Immune><Immune mediated therapy><Immunes><Immunologically Directed Therapy><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapy><Incidence><Intermediary Metabolism><L arginine amidinohydrolase><L-Arginine><L-Ornithine carboxy-lyase><Ligands><Liver Immunoregulatory Protein><Liver-Derived Inhibitory Protein><Macrophage><Malignant Breast Neoplasm><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Mammary Cancer><Mammary Gland Parenchyma><Mammary Gland Tissue><Mammary Neoplasms><Measures><Mediating><Metabolic Diseases><Metabolic Disorder><Metabolic Pathway><Metabolic Processes><Metabolism><Methods><Mice><Mice Mammals><Modern Man><Molecular Tumor Suppression><Murine><Mus><Mφ><NEU Oncogene><NEU protein><NO Synthase><Nature><Nitric Oxide Synthase><Nitric-Oxide Synthetase><Oncogene ErbB2><Ornithine Carbamoyltransferase><Ornithine Carbamylphosphate Transferase><Ornithine Carboxy-lyase><Ornithine Decarboxylase><Ornithine Transcarbamylase><Outcome><PD-L1><PDL-1><PDL1><Pathway interactions><Phenylalanine hydroxylase deficiency><Phenylketonurias><Polyamine Compound><Polyamine Synthesis Inhibition><Polyamines><Prevention><Production><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Public Health><Reaction><Refractory><Reporting><Safety><Shunt><Shunt Device><THBP><TKR1><Testing><Thesaurismosis><Time><Tissue Growth><Tumor Cell><Tumor Promotion><Tumor Suppression><Tumor-associated macrophages><Work><adjuvant treatment><anti-cancer immunotherapy><anti-tumor effect><anticancer immunotherapy><antitumor effect><arginase><arginine amidinase><argininosuccinate lyase><argininosuccinate synthase><arginosuccinate lyase><arginosuccinate synthase><breast tumor cell><c-erbB-2><c-erbB-2 Genes><c-erbB-2 Proto-Oncogenes><canavanase><cancer cell><cancer immunotherapy><cancer microenvironment><cancer type><cell growth><citrulline phosphorylase><cofactor><determine efficacy><drug resistant><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><erbB-2 Genes><evaluate efficacy><examine efficacy><herstatin><immune microenvironment><immune suppression><immune suppressive activity><immune suppressive function><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immuno therapy><immunogenicity><immunosuppressive activity><immunosuppressive function><immunosuppressive microenvironment><immunosuppressive response><immunosuppressive tumor microenvironment><immunotherapy for cancer><immunotherapy of cancer><improved><innovate><innovation><innovative><malignancy><malignant breast tumor><mammary cancer prevention><mammary tumor><mammary tumor prevention><metabolism disorder><mouse model><murine model><neoplasm/cancer><neoplastic cell><neu Genes><novel><ontogeny><pathway><phenylalaninemia><prevent><prevent breast cancer><preventing><programmed cell death ligand 1><programmed cell death protein ligand 1><protein death-ligand 1><resistance to Drug><resistant to Drug><sepiapterin><shunts><side effect><systemic toxicity><tetrahydrobiopterin><translational impact><tumor><tumor growth><tumor immune microenvironment><tumor microenvironment><tumor-immune system interactions>