Targeting Amino Acid Metabolism in Glioblastoma

ABSTRACT Glioblastomas rank among the most lethal of all human cancers. Current therapy includes maximal surgical resection, followed by combined radiotherapy and oral chemotherapy (temozolomide), and adjuvant temozolomide. However, current glioblastoma therapy offers only palliation. Median survival for glioblastoma patients has been reported to be 15-21 months, but these data are derived from patients with favorable age and performance status. Glioblastoma ranks among the human cancers most thoroughly studied, yet precision medicine efforts have demonstrated very limited efficacy. Like many cancers, glioblastomas display altered metabolism that promotes tumor growth, often through the generation of metabolites that promote epigenetic reprogramming. In the current proposal, we focus on the role of specific essential amino acids that appear to the preferentially taken up by brain tumor cells. Upon cellular entry, amino acids can undergo catabolism to generate bioactive intermediates that can alter the chromatin landscape and modulate tumor- immune interactions. Based on this background, we investigated differential expression of metabolic pathways and amino acid levels between glioblastoma cells and neural stem cells, revealing critical selective dependencies in tumor cells due to both altered gene expression and genetic lesions. As a result, glioblastoma cells suppress the anti-tumor immune response. In the proposed studies, we will investigate the molecular and cell biology mechanisms through which selective amino acid metabolism regulates brain tumor growth and immune interplay. Systems to be used include patient-derived cultures, organoids, and xenografts to determine the molecular determinants of amino acid catabolism and epigenetic reprogramming. To translate these efforts into novel preclinical paradigms, we propose to use dietary manipulations that have been developed for treatment of inborn errors of metabolism, including those that affect the brain. These dietary interventions can potentially be combined with other therapies, including targeted therapies and immune checkpoint inhibitors, to target glioblastomas. Collectively, the proposed studies will lay the foundation for improved understanding of tumor metabolism in brain tumor biology with possible application to oncologic care.