Inhibition of mTORC1 in pediatric low-grade glioma depletes glutathione and therapeutically synergizes with carboplatin

Neuro-oncology
Brad PooreEric H Raabe

Abstract

Pediatric low-grade glioma (pLGG) often initially responds to front-line therapies such as carboplatin, but more than 50% of treated tumors eventually progress and require additional therapy. With the discovery that pLGG often contains mammalian target of rapamycin (mTOR) activation, new treatment modalities and combinations are now possible for patients. The purpose of this study was to determine if carboplatin is synergistic with the mTOR complex 1 inhibitor everolimus in pLGG. We treated 4 pLGG cell lines and 1 patient-derived xenograft line representing various pLGG genotypes, including neurofibromatosis type 1 loss, proto-oncogene B-Raf (BRAF)-KIAA1549 fusion, and BRAFV600E mutation, with carboplatin and/or everolimus and performed assays for growth, cell proliferation, and cell death. Immunohistochemistry as well as in vivo and in vitro metabolomics studies were also performed. Carboplatin synergized with everolimus in all of our 4 pLGG cell lines (combination index <1 at Fa 0.5). Combination therapy was superior at inhibiting tumor growth in vivo. Combination treatment increased levels of apoptosis as well as gamma-H2AX phosphorylation compared with either agent alone. Everolimus treatment suppressed the conversion of gl...Continue Reading

References

Aug 16, 2001·Proceedings of the National Academy of Sciences of the United States of America·M S NeshatC L Sawyers
Apr 26, 2007·Chemical Reviews·Yongwon Jung, Stephen J Lippard
Jul 13, 2007·Nature Reviews. Cancer·Lloyd Kelland
Oct 20, 2007·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Maryam FouladiWayne L Furman
Aug 22, 2008·Journal of Neuropathology and Experimental Neurology·Eli E BarCharles G Eberhart
Aug 30, 2008·Cytometry. Part B, Clinical Cytometry·Peggy L Olive, Judit P Banáth
Jun 6, 2009·Expert Review of Anticancer Therapy·Stéphane OudardFlorian Scotte
Sep 29, 2009·Cancer Chemotherapy and Pharmacology·Terence O'ReillyH A Lane
Oct 21, 2009·Journal of Child Neurology·Angela J Sievert, Michael J Fisher
May 18, 2010·Neuro-oncology·David AkhavanPaul S Mischel
Sep 2, 2010·Pediatric Blood & Cancer·E Anders KolbMalcolm A Smith
Nov 6, 2010·Analytical Chemistry·Eugene MelamudJoshua D Rabinowitz
Feb 11, 2011·The New England Journal of Medicine·James C YaoUNKNOWN RAD001 in Advanced Neuroendocrine Tumors, Third Trial (RADIANT-3) Study Group
May 3, 2011·Trends in Biochemical Sciences·Michelle C MendozaJohn Blenis
Jun 4, 2011·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Eric H RaabeCharles G Eberhart
Dec 23, 2011·The American Journal of Pathology·Xuefeng LiuRichard Schlegel
Apr 17, 2012·Cell·Mathieu Laplante, David M Sabatini
Jun 6, 2012·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Joann L AterIan F Pollack
Apr 30, 2013·Cancer·Keita TerashimaMurali Chintagumpala
Jul 25, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Eric RaabeKenneth J Cohen
Oct 18, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Hemant K BidPeter J Houghton
Jul 24, 2014·CNS Oncology·Fausto J Rodriguez, Eric H Raabe
Dec 24, 2014·Neuro-oncology·Aparna KaulDavid H Gutmann
Jan 13, 2015·Journal of Neuropathology and Experimental Neurology·Harpreet KaurEric H Raabe
Jul 15, 2015·Pharmacology Research & Perspectives·Julie Foucquier, Mickael Guedj
Sep 19, 2015·Annals of Neurology·David N FranzDarcy A Krueger
Mar 26, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Allison R HanafordEric H Raabe
Apr 9, 2016·Journal of Basic and Clinical Pharmacy·Anroop B Nair, Shery Jacob
Aug 31, 2016·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Alvaro LassalettaEric Bouffet
Aug 9, 2017·The Journal of Experimental Medicine·Peer W F KarmausHongbo Chi

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Citations

Oct 8, 2020·Journal of Neuro-oncology·Florian SeltTill Milde
Jul 14, 2019·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Sabrina Z WangJeffrey A Rubens
Jun 3, 2021·International Journal of Molecular Sciences·Jaewan JeonHae Yu Kim
Jun 3, 2021·Metabolites·Karol JarochBarbara Bojko

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