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

Overview

Journal Clin Cancer Res

Specialty Oncology

Date 2019 Jul 14

PMID 31300448

Citations 16

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

Affiliations

Soon will be listed here.

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 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.

Citing Articles

Case report: Molecular characterization of adult atypical teratoid rhabdoid tumor and review of the literature.

Hernandez-Rovira M, Connor M, Osorio R, Russler-Germain E, Schmidt R, Johnson G Front Oncol. 2025; 15:1510439.

PMID: 40052132 PMC: 11882417. DOI: 10.3389/fonc.2025.1510439.

Metabolic profiling of patient-derived organoids reveals nucleotide synthesis as a metabolic vulnerability in malignant rhabdoid tumors.

Kes M, Morales-Rodriguez F, Zaal E, de Souza T, Proost N, van de Ven M Cell Rep Med. 2024; 6(1):101878.

PMID: 39708810 PMC: 11866552. DOI: 10.1016/j.xcrm.2024.101878.

Establishment and Characterization of Three Human Ocular Adnexal Sebaceous Carcinoma Cell Lines.

Lee S, Peterson C, Wang K, Alaali L, Eshleman J, Mahoney N Int J Mol Sci. 2024; 25(18).

PMID: 39337668 PMC: 11432008. DOI: 10.3390/ijms251810183.

Roles of Glutathione and AP-1 in the Enhancement of Vitamin D-Induced Differentiation by Activators of the Nrf2 Signaling Pathway in Acute Myeloid Leukemia Cells.

Jramne-Saleem Y, Danilenko M Int J Mol Sci. 2024; 25(4).

PMID: 38396960 PMC: 10889780. DOI: 10.3390/ijms25042284.

Glutamine mimicry suppresses tumor progression through asparagine metabolism in pancreatic ductal adenocarcinoma.

Recouvreux M, Grenier S, Zhang Y, Esparza E, Lambies G, Galapate C Nat Cancer. 2023; 5(1):100-113.

PMID: 37814011 PMC: 10956382. DOI: 10.1038/s43018-023-00649-1.

References

Viswanathan S, Powers J, Einhorn W, Hoshida Y, Ng T, Toffanin S . Lin28 promotes transformation and is associated with advanced human malignancies. Nat Genet. 2009; 41(7):843-8. PMC: 2757943. DOI: 10.1038/ng.392. View

Melamud E, Vastag L, Rabinowitz J . Metabolomic analysis and visualization engine for LC-MS data. Anal Chem. 2010; 82(23):9818-26. PMC: 5748896. DOI: 10.1021/ac1021166. View

Lee R, Stewart C, Carter S, Ambrogio L, Cibulskis K, Sougnez C . A remarkably simple genome underlies highly malignant pediatric rhabdoid cancers. J Clin Invest. 2012; 122(8):2983-8. PMC: 3408754. DOI: 10.1172/JCI64400. View

Gross M, Demo S, Dennison J, Chen L, Chernov-Rogan T, Goyal B . Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol Cancer Ther. 2014; 13(4):890-901. DOI: 10.1158/1535-7163.MCT-13-0870. View

Alimova I, Pierce A, Danis E, Donson A, Birks D, Griesinger A . Inhibition of MYC attenuates tumor cell self-renewal and promotes senescence in SMARCB1-deficient Group 2 atypical teratoid rhabdoid tumors to suppress tumor growth in vivo. Int J Cancer. 2018; 144(8):1983-1995. DOI: 10.1002/ijc.31873. View

Chi S, Zimmerman M, Yao X, Cohen K, Burger P, Biegel J . Intensive multimodality treatment for children with newly diagnosed CNS atypical teratoid rhabdoid tumor. J Clin Oncol. 2008; 27(3):385-9. PMC: 2645855. DOI: 10.1200/JCO.2008.18.7724. View

Hanahan D, Weinberg R . Hallmarks of cancer: the next generation. Cell. 2011; 144(5):646-74. DOI: 10.1016/j.cell.2011.02.013. View

Packer R, Lange B, Ater J, Nicholson H, Allen J, Walker R . Carboplatin and vincristine for recurrent and newly diagnosed low-grade gliomas of childhood. J Clin Oncol. 1993; 11(5):850-6. DOI: 10.1200/JCO.1993.11.5.850. View

Martelli L, Di Mario F, Botti P, Ragazzi E, Martelli M, Kelland L . Accumulation, platinum-DNA adduct formation and cytotoxicity of cisplatin, oxaliplatin and satraplatin in sensitive and resistant human osteosarcoma cell lines, characterized by p53 wild-type status. Biochem Pharmacol. 2007; 74(1):20-7. DOI: 10.1016/j.bcp.2007.03.025. View

10.

Takahashi K, Yamanaka S . Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006; 126(4):663-76. DOI: 10.1016/j.cell.2006.07.024. View

11.

Stewart D . Mechanisms of resistance to cisplatin and carboplatin. Crit Rev Oncol Hematol. 2007; 63(1):12-31. DOI: 10.1016/j.critrevonc.2007.02.001. View

12.

Arcaro A, Doepfner K, Boller D, Guerreiro A, Shalaby T, Jackson S . Novel role for insulin as an autocrine growth factor for malignant brain tumour cells. Biochem J. 2007; 406(1):57-66. PMC: 1948991. DOI: 10.1042/BJ20070309. View

13.

Alimova I, Pierce A, Harris P, Donson A, Birks D, Prince E . Targeting Polo-like kinase 1 in SMARCB1 deleted atypical teratoid rhabdoid tumor. Oncotarget. 2017; 8(57):97290-97303. PMC: 5722562. DOI: 10.18632/oncotarget.21932. View

14.

Piskounova E, Polytarchou C, Thornton J, LaPierre R, Pothoulakis C, Hagan J . Lin28A and Lin28B inhibit let-7 microRNA biogenesis by distinct mechanisms. Cell. 2011; 147(5):1066-79. PMC: 3227872. DOI: 10.1016/j.cell.2011.10.039. View

15.

Shim K, Xi G, Farnell B, Kim D, Tsurubuchi T, Tomita T . Epigenetic modification after inhibition of IGF-1R signaling in human central nervous system atypical teratoid rhabdoid tumor (AT/RT). Childs Nerv Syst. 2013; 29(8):1245-51. DOI: 10.1007/s00381-013-2087-7. View

16.

Wang X, Cao L, Wang Y, Wang X, Liu N, You Y . Regulation of let-7 and its target oncogenes (Review). Oncol Lett. 2012; 3(5):955-960. PMC: 3389667. DOI: 10.3892/ol.2012.609. View

17.

Kaur H, Hutt-Cabezas M, Weingart M, Xu J, Kuwahara Y, Erdreich-Epstein A . The chromatin-modifying protein HMGA2 promotes atypical teratoid/rhabdoid cell tumorigenicity. J Neuropathol Exp Neurol. 2015; 74(2):177-85. PMC: 4695975. DOI: 10.1097/NEN.0000000000000161. View

18.

Sullivan M, Nelson J, Feldman S, Van Nguyen B . Pharmacokinetic and phase I study of intravenous DON (6-diazo-5-oxo-L-norleucine) in children. Cancer Chemother Pharmacol. 1988; 21(1):78-84. DOI: 10.1007/BF00262746. View

19.

Hanaford A, Archer T, Price A, Kahlert U, Maciaczyk J, Nikkhah G . DiSCoVERing Innovative Therapies for Rare Tumors: Combining Genetically Accurate Disease Models with In Silico Analysis to Identify Novel Therapeutic Targets. Clin Cancer Res. 2016; 22(15):3903-14. PMC: 5055054. DOI: 10.1158/1078-0432.CCR-15-3011. View

20.

Kang M, Smith M, Morton C, Keshelava N, Houghton P, Reynolds C . National Cancer Institute pediatric preclinical testing program: model description for in vitro cytotoxicity testing. Pediatr Blood Cancer. 2010; 56(2):239-49. PMC: 3005554. DOI: 10.1002/pbc.22801. View