THE GLUTAMINE TRANSPORTER AND CANDIDATE DIAGNOSTIC AND THERAPEUTIC TARGET SLC1A5 IS ASSOCIATED WITH SUBTYPE-SPECIFIC METABOLIC PHENOTYPES AND TUMOR PROGNOSIS IN PEDIATRIC BRAIN CANCERS

Abstract Glutamine transporters play an important role in supporting increased tumor nutritional demands relative to non-cancerous cells, often through overexpression of the solute carrier (SLC) family of membrane transporters. Preclinical studies in adult cancers demonstrate that targeting glutamine addiction via SLC1A5 inhibition results in growth-inhibitory and tumoricidal effects. Given their relatively higher expression in cancer versus normal brain tissue, SLC transporters represent compelling targets for molecularly-targeted radiation and application of available prognostic amino-acid PET imaging probes. However, the role of SLC transporters in pediatric brain cancers has yet to be investigated. We aimed to understand the relationship of SLC transporter expression with pediatric brain tumor subtypes and their potential prognostic significance using data from the Pediatric Brain Tumor Atlas (PBTA). Using the expression of amino acid transporter genes in ensemble survival models (Reactome: R-HSA-352230), we found that elevated expression of glutamine transporters (SLC1A5, SLC7A5, SLC7A11, SLC38A5, SLC38A3) predicted shorter progression-free survival (PFS) in low-grade gliomas (LGGs) and poorer overall survival in pediatric ependymomas, high-grade gliomas (HGGs), and medulloblastomas. We focused specifically on SLC1A5 given the availability of imaging probes (18 F-Fluoroglutamine and 18F-Fluciclovine) for the corresponding amino acid transporter (ASCT2). Through transcriptome-based consensus clustering, we found that supratentorial, RELA fusion-positive ependymomas and sonic hedgehog-activated medulloblastomas were over-represented among clusters expressing higher levels of SLC1A5 (p = 3.38e-7 and p = 2.18-26, respectively). Kaplan-Meier analysis found that higher expression of SLC1A5 was associated with shorter OS in ependymoma and medulloblastoma (p = 9.8e-4 and p = 0.032) and shorter PFS in LGG (p = 0.022). Gene set analysis showed higher expression and network rewiring of amino acid, lipid, and immune pathways in SLC1A5-high expressing clusters. Our work demonstrates that glutamine transporters, particularly SLC1A5, represent compelling targets in pediatric brain cancers that warrant further investigation for molecularly-targeted treatment and amino-acid PET imaging.