Abstract 5267: Unbiased metabolic profiling of atypical teratoid/rhabdoid tumors predicts sensitivity to the glutamine metabolic inhibitor 6-diazo-5-oxo-L-norleucine

Abstract

Atypical teratoid rhabdoid tumors (AT/RT) are deadly tumors of infancy in need of new, targeted therapies. Molecular analyses have revealed 3 epigenetically distinct subgroups of AT/RT. High MYC-expressing tumors are a particularly aggressive subgroup, with a 5-year median survival of 18.5%. MYC is difficult to directly target given large, flat, featureless protein-protein binding sites. We performed the first unbiased metabolic profile of AT/RT cell models by high-performance liquid chromatography-mass spectrometry. This study revealed that high MYC-expressing AT/RT have a unique metabolic profile (Partial Least Squares-Discriminant Analysis). Pathway analysis highlights a dependence on glutamine metabolism in high-MYC expressing AT/RT. High MYC-expressing cell lines grow poorly in glutamine-free media compared to low-MYC cell lines (MTS assay, glutamine-free media vs normal media). Due to this dependence on glutamine metabolism, we hypothesized that high-MYC expressing AT/RT would be especially sensitive to glutamine metabolic inhibitors. We show that the glutamine analogue, 6-diazo-5-oxo-L-norleucine (DON) slows high-MYC expressing AT/RT cell growth, induces high rates of apoptosis, and improves survival in orthotopic mouse models of high-MYC expressing AT/RT (p =0.0027 by log-rank test). In contrast, low-MYC expressing models are relatively insensitive to DON. In uniformly labeled glutamine metabolic analyses of AT/RT cells, DON treatment led to depletion of glutathione levels by preventing the production of glutamate. DON treatment synergized with carboplatin to kill AT/RT cells in vitro and extend the life of mice bearing AT/RT orthotopic xenografts (p Citation Format: Sabrina Z. Wang, Brad Poore, Jesse Alt, Antoinette Price, Sariah Allen, Brent Orr, Rana Rais, Barbara Slusher, Charles Eberhart, Eric H. Raabe, Jeffrey H. Rubens. Unbiased metabolic profiling of atypical teratoid/rhabdoid tumors predicts sensitivity to the glutamine metabolic inhibitor 6-diazo-5-oxo-L-norleucine [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 5267.