Abstract 3519: Disrupting glutamine metabolism depletes glutathione and sensitizes atypical teratoid/rhabdoid tumor to carboplatin

Abstract

Abstract Atypical teratoid rhabdoid tumors (AT/RT) are the most common malignant brain tumors of infancy. Recent high-throughput molecular analyses identified 3 distinct subgroups of AT/RT. Preliminary studies show that subgroups with elevated MYC expressions are particularly aggressive, with 18.5% 5-year survival. MYC is challenging to directly target, but MYC increases tumor cells' reliance on glutamine for their metabolic demands. We hypothesize that MYC-driven ATRT can be targeted by inhibiting glutamine metabolism. 6-Diazo-5-oxo L-norleucine (DON) is a glutamine analogue that was well tolerated in a phase I pediatric clinical trial, but DON has never been tested in MYC-driven pediatric tumors. Approximately 1/3 of human AT/RT express high MYC protein (immunohistochemistry for c-MYC expression on 22 human AT/RT, H-score > 1 standard deviation over the median for high c-MYC expression). DON slows cell growth and induces apoptosis in high MYC-expressing AT/RT while low MYC-expressing cells are resistant (MTS assay and Western blot for c-PARP, respectively). Transducing low MYC-expressing cell lines with lentivirus with MYC plasmid to force MYC expression confers sensitivity to DON therapy (decreased cell growth per MTS assay, increased apoptosis per Western for c-PARP). DON administered intraperitoneally 30mg/kg weekly nearly doubles median survival in orthotopic xenograft models of AT/RT (p<0.001 by log rank test; median survival extended from 21 to 36 days). Metabolic flux experiments tracing 15N and 13C labeled glutamine reveal that DON reduces intracellular glutathione. We combine DON with carboplatin because glutathione is critical for detoxification of carboplatin and find that the combination works synergistically to further slow cell growth and induce higher rates of apoptosis (MTS assay, MUSE Cell Viability Assay). This study takes a novel approach to targeting cancer metabolism and serves as the first targeted therapeutic strategy addressing the MYC-expressing subgroup of AT/RT. These findings support the rationale for potential future clinical trials testing glutamine analogues against the MYC subgroup of AT/RT as well as other deadly MYC-driven tumors. Citation Format: Sabrina Z. Wang, Brad Poore, Jesse Alt, Rana Rais, Sariah Allen, Brent Orr, Barbara Slusher, Charles Eberhart, Eric Raabe, Jeffrey Rubens. Disrupting glutamine metabolism depletes glutathione and sensitizes atypical teratoid/rhabdoid tumor to carboplatin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3519.