Unbiased Metabolic Profiling Predicts Sensitivity of High MYC-Expressing Atypical Teratoid/Rhabdoid Tumors to Glutamine Inhibition with 6-Diazo-5-Oxo-L-Norleucine.

Abstract

PURPOSE:

Atypical teratoid/rhabdoid tumors (AT/RT) are aggressive infantile brain tumors with poor survival. Recent advancements have highlighted significant molecular heterogeneity in AT/RT with an aggressive subgroup featuring overexpression of the MYC proto-oncogene. We perform the first comprehensive metabolic profiling of patient-derived AT/RT cell lines to identify therapeutic susceptibilities in high MYC-expressing AT/RT.

EXPERIMENTAL DESIGN:

Metabolites were extracted from AT/RT cell lines and separated in ultra-high performance liquid chromatography mass spectrometry. Glutamine metabolic inhibition with 6-diazo-5-oxo-L-norleucine (DON) was tested with growth and cell death assays and survival studies in orthotopic mouse models of AT/RT. Metabolic flux analysis was completed to identify combination therapies to act synergistically to improve survival in high MYC AT/RT.

RESULTS:

Unbiased metabolic profiling of AT/RT cell models identified a unique dependence of high MYC AT/RT on glutamine for survival. The glutamine analogue, DON, selectively targeted high MYC cell lines, slowing cell growth, inducing apoptosis, and extending survival in orthotopic mouse models of AT/RT. Metabolic flux experiments with isotopically labeled glutamine revealed DON inhibition of glutathione (GSH) synthesis. DON combined with carboplatin further slowed cell growth, induced apoptosis, and extended survival in orthotopic mouse models of high MYC AT/RT.

CONCLUSIONS:

Unbiased metabolic profiling of AT/RT identified susceptibility of high MYC AT/RT to glutamine metabolic inhibition with DON therapy. DON inhibited glutamine-dependent synthesis of GSH and synergized with carboplatin to extend survival in high MYC AT/RT. These findings can rapidly translate into new clinical trials to improve survival in high MYC AT/RT.

• Authors: Sabrina Z Wang, Brad Poore, Jesse Alt, Antoinette Price, Sariah J Allen, Allison R Hanaford, Harpreet Kaur, Brent A Orr, Barbara S Slusher, Charles G Eberhart, Eric H Raabe, Jeffrey A Rubens
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 25 Issue 19 Pg. 5925-5936 (10 01 2019) ISSN: 1557-3265 [Electronic] United States
• PMID: 31300448 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2019 American Association for Cancer Research.

Chemical References

• Antimetabolites, Antineoplastic
• MAS1 protein, human
• MYC protein, human
• Proto-Oncogene Mas
• Proto-Oncogene Proteins c-myc
• Diazooxonorleucine
• Glutamine

Topics

• Animals
• Antimetabolites, Antineoplastic (pharmacology)
• Apoptosis (drug effects)
• Cell Proliferation (drug effects)
• Diazooxonorleucine (pharmacology)
• Female
• Glutamine (antagonists & inhibitors, metabolism)
• Humans
• Metabolome (drug effects)
• Mice
• Mice, Nude
• Proto-Oncogene Mas
• Proto-Oncogene Proteins c-myc (metabolism)
• Rhabdoid Tumor (drug therapy, metabolism, pathology)
• Teratoma (drug therapy, metabolism, pathology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays