Abstract 5280: Branched chain amino acids represent indispensible metabolic substrates in glioblastoma

Abstract

Abstract Glioblastoma (GBM) is an aggressive brain tumor with limited treatment options. Considerable advances have been made in understanding the genetic alterations driving these tumors, however, the metabolic alterations and mechanisms underlying these aggressive phenotypes remain unclear. We performed global metabolomic profiling of patient derived low-grade astrocytoma (LGA, n= 28) and GBM (n=80). Hierarchical clustering (HC) identified amino acid (AA) metabolism as a dominant metabolic node in GBM compared to LGA. Considerable inter-tumoral heterogeneity of AA metabolism was observed in GBM, with HC identifying two clearly distinct metabolic subtypes consisting of increased and decreased concentrations of AA and their metabolic intermediates. VIP analysis identified the accumulation of branched chain amino acids (BCAA)- leucine, valine and isoleucine as the top ranked metabolites differentiating these subtypes. Based on this, GBMs were classified as BCAA-high and BCAA-low. BCAA-high GBM was enriched with mesenchymal and classical subtypes while BCAA-low GBM was enriched with proneural and neural subtypes. Integrative analysis coupling these metabolic signatures with gene expression profiling performed on matched tissue demonstrated upregulation of BCAA metabolism-associated genes in BCAA-high GBM, along with global transcriptional programs designed to activate cell cycle progression. When extended into molecular subtype specific preclinical models, we demonstrated that BCAA were indispensible for survival of mesenchymal GBM cells, which was independent of the presence or absence of other non-essential and essential amino acids. Further, these cells were able to maintain long-term survival in a dormant state when grown in media devoid of all essential and non-essential AA other than BCAA and glutamine. Knockdown of key enzymes in BCAA metabolism led to robust cytotoxicity in this model, underscoring the importance of BCAA in GBM survival. Ongoing studies are designed to determine the biologic consequence and intermediary metabolism of BCAA in GBM. Collectively these results identify BCAA metabolism as a therapeutic target in GBM. Citation Format: Antony H. Prabhu, Shiva Kant, Pravin Kesarwani, Prakash Chinnaiyan. Branched chain amino acids represent indispensible metabolic substrates in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5280.