Genetically and metabolically defining high-risk neuroblastoma to exploit effective therapeutic strategies

Summary: Neuroblastoma is the most common type of cancer in infancy and causes as much as 15% of childhood cancer mortality. The 5-year survival rates for patients with high-risk neuroblastoma remain at about 50% even with intensive multimodal therapies. Developing novel precision- and immuno-therapies is imperative to augment current therapy with minimal toxicity, prevent disease recurrence, and achieve durable cures in high-risk neuro- blastoma patients. Thisproposal addresses major obstacles to understanding oncogenesis and developingnovel neuroblastoma therapies, including establishing and characterizing clinically relevant immunocompetent mouse models of high-risk neuroblastoma, targeting metabolic vulnerabilities, and reprogramming the immune-suppres- sive tumor microenvironment. We have recently developed neuroblastoma genetically engineered mouse mod- els (GEMMs) that resemble genomic, histological, and immunogenic characteristics of human high-risk neuro- blastoma. We analyzed metabolic gene signatures in high-risk human neuroblastoma and metabolic flux in neu- roblastoma-bearing animal models. We revealed that γ-aminobutyric acid (GABA) is a characteristic metabolite produced, metabolized, and excreted by neuroblastoma. GABA enhances mitochondria metabolism in neuro- blastoma and is excreted as a paracrine molecule, acting on T cells through GABA receptors to suppress CD8 T-cell effector functions. Accordingly, modulating the GABA metabolism reduces neuroblastomacell proliferation and immune-suppressive capacity. Hence, we hypothesize that GABA metabolism cooperates with onco- genic signaling to promote tumorigenesis and foster the immune-suppressive microenvironment in high-risk neuroblastoma; therapeutically targeting GABA metabolism may maximize immunotherapies. To test our hypothesis, we propose the following specific aims: 1) Determine how GABA metabolism controls and impacts neuroblastoma development; 2) Develop clinically relevant immune-competent neuroblastoma mouse models and test GABA-targeting strategies to improve immunotherapy. Our proposed innovative study is among the first major attempts to modulate the tumor’s immune-suppressive metabolic environment, which will help better understand how the altered metabolic landscape of the pediatric tumor’s microenvironment im- pacts anti-tumor immunity. Project Number: 1R01CA299046-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Ruoning Wang | Institution: RESEARCH INST NATIONWIDE CHILDREN'S HOSP, COLUMBUS, OH | Award Amount: $608,558 | Activity Code: R01 | Study Section: Cancer Cell Biology Study Section[CCB] View on NIH RePORTER: https://reporter.nih.gov/project-details/11293506