Cargando…

Novel mTORC1 Inhibitors Kill Glioblastoma Stem Cells

Glioblastoma (GBM) is an aggressive tumor of the brain, with an average post-diagnosis survival of 15 months. GBM stem cells (GBMSC) resist the standard-of-care therapy, temozolomide, and are considered a major contributor to tumor resistance. Mammalian target of rapamycin Complex 1 (mTORC1) regulat...

Descripción completa

Detalles Bibliográficos
Autores principales: Sandoval, Jose A., Tomilov, Alexey, Datta, Sandipan, Allen, Sonia, O’Donnell, Robert, Sears, Thomas, Woolard, Kevin, Kovalskyy, Dmytro, Angelastro, James M., Cortopassi, Gino
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761300/
https://www.ncbi.nlm.nih.gov/pubmed/33255358
http://dx.doi.org/10.3390/ph13120419
_version_ 1783627536248340480
author Sandoval, Jose A.
Tomilov, Alexey
Datta, Sandipan
Allen, Sonia
O’Donnell, Robert
Sears, Thomas
Woolard, Kevin
Kovalskyy, Dmytro
Angelastro, James M.
Cortopassi, Gino
author_facet Sandoval, Jose A.
Tomilov, Alexey
Datta, Sandipan
Allen, Sonia
O’Donnell, Robert
Sears, Thomas
Woolard, Kevin
Kovalskyy, Dmytro
Angelastro, James M.
Cortopassi, Gino
author_sort Sandoval, Jose A.
collection PubMed
description Glioblastoma (GBM) is an aggressive tumor of the brain, with an average post-diagnosis survival of 15 months. GBM stem cells (GBMSC) resist the standard-of-care therapy, temozolomide, and are considered a major contributor to tumor resistance. Mammalian target of rapamycin Complex 1 (mTORC1) regulates cell proliferation and has been shown by others to have reduced activity in GBMSC. We recently identified a novel chemical series of human-safe piperazine-based brain-penetrant mTORC1-specific inhibitors. We assayed the piperazine-mTOR binding strength by two biophysical measurements, biolayer interferometry and field-effect biosensing, and these confirmed each other and demonstrated a structure–activity relationship. As mTORC1 is altered in human GBMSC, and as mTORC1 inhibitors have been tested in previous GBM clinical trials, we tested the killing potency of the tightest-binding piperazines and observed that these were potent GBMSC killers. GBMSCs are resistant to the standard-of-care temozolomide therapy, but temozolomide supplemented with tight-binding piperazine meclizine and flunarizine greatly enhanced GBMSC death over temozolomide alone. Lastly, we investigated IDH1-mutated GBMSC mutations that are known to affect mitochondrial and mTORC1 metabolism, and the tight-binding meclizine provoked ‘synthetic lethality’ in IDH1-mutant GBMSCs. In other words, IDH1-mutated GBMSC showed greater sensitivity to the coadministration of temozolomide and meclizine. These data tend to support a novel clinical strategy for GBM, i.e., the co-administration of meclizine or flunarizine as adjuvant therapy in the treatment of GBM and IDH1-mutant GBM.
format Online
Article
Text
id pubmed-7761300
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-77613002020-12-26 Novel mTORC1 Inhibitors Kill Glioblastoma Stem Cells Sandoval, Jose A. Tomilov, Alexey Datta, Sandipan Allen, Sonia O’Donnell, Robert Sears, Thomas Woolard, Kevin Kovalskyy, Dmytro Angelastro, James M. Cortopassi, Gino Pharmaceuticals (Basel) Article Glioblastoma (GBM) is an aggressive tumor of the brain, with an average post-diagnosis survival of 15 months. GBM stem cells (GBMSC) resist the standard-of-care therapy, temozolomide, and are considered a major contributor to tumor resistance. Mammalian target of rapamycin Complex 1 (mTORC1) regulates cell proliferation and has been shown by others to have reduced activity in GBMSC. We recently identified a novel chemical series of human-safe piperazine-based brain-penetrant mTORC1-specific inhibitors. We assayed the piperazine-mTOR binding strength by two biophysical measurements, biolayer interferometry and field-effect biosensing, and these confirmed each other and demonstrated a structure–activity relationship. As mTORC1 is altered in human GBMSC, and as mTORC1 inhibitors have been tested in previous GBM clinical trials, we tested the killing potency of the tightest-binding piperazines and observed that these were potent GBMSC killers. GBMSCs are resistant to the standard-of-care temozolomide therapy, but temozolomide supplemented with tight-binding piperazine meclizine and flunarizine greatly enhanced GBMSC death over temozolomide alone. Lastly, we investigated IDH1-mutated GBMSC mutations that are known to affect mitochondrial and mTORC1 metabolism, and the tight-binding meclizine provoked ‘synthetic lethality’ in IDH1-mutant GBMSCs. In other words, IDH1-mutated GBMSC showed greater sensitivity to the coadministration of temozolomide and meclizine. These data tend to support a novel clinical strategy for GBM, i.e., the co-administration of meclizine or flunarizine as adjuvant therapy in the treatment of GBM and IDH1-mutant GBM. MDPI 2020-11-24 /pmc/articles/PMC7761300/ /pubmed/33255358 http://dx.doi.org/10.3390/ph13120419 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sandoval, Jose A.
Tomilov, Alexey
Datta, Sandipan
Allen, Sonia
O’Donnell, Robert
Sears, Thomas
Woolard, Kevin
Kovalskyy, Dmytro
Angelastro, James M.
Cortopassi, Gino
Novel mTORC1 Inhibitors Kill Glioblastoma Stem Cells
title Novel mTORC1 Inhibitors Kill Glioblastoma Stem Cells
title_full Novel mTORC1 Inhibitors Kill Glioblastoma Stem Cells
title_fullStr Novel mTORC1 Inhibitors Kill Glioblastoma Stem Cells
title_full_unstemmed Novel mTORC1 Inhibitors Kill Glioblastoma Stem Cells
title_short Novel mTORC1 Inhibitors Kill Glioblastoma Stem Cells
title_sort novel mtorc1 inhibitors kill glioblastoma stem cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761300/
https://www.ncbi.nlm.nih.gov/pubmed/33255358
http://dx.doi.org/10.3390/ph13120419
work_keys_str_mv AT sandovaljosea novelmtorc1inhibitorskillglioblastomastemcells
AT tomilovalexey novelmtorc1inhibitorskillglioblastomastemcells
AT dattasandipan novelmtorc1inhibitorskillglioblastomastemcells
AT allensonia novelmtorc1inhibitorskillglioblastomastemcells
AT odonnellrobert novelmtorc1inhibitorskillglioblastomastemcells
AT searsthomas novelmtorc1inhibitorskillglioblastomastemcells
AT woolardkevin novelmtorc1inhibitorskillglioblastomastemcells
AT kovalskyydmytro novelmtorc1inhibitorskillglioblastomastemcells
AT angelastrojamesm novelmtorc1inhibitorskillglioblastomastemcells
AT cortopassigino novelmtorc1inhibitorskillglioblastomastemcells