RT Journal Article
SR Electronic
T1 Novel mTORC1 inhibitors kill Glioblastoma stem cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.06.17.157735
DO 10.1101/2020.06.17.157735
A1 Jose Sandoval
A1 Alexey Tomilov
A1 Sandipan Datta
A1 Sonia Allen
A1 Robert O’Donnell
A1 James Angelastro
A1 Gino Cortopassi
YR 2020
UL http://biorxiv.org/content/early/2020/06/19/2020.06.17.157735.abstract
AB Glioblastoma Multiforme (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. 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 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. Since mTORC1 is reduced 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 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, the tight-binding Meclizine provoked ‘synthetic lethality’ in IDH1-mutant GBMSCs. 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.Competing Interest StatementThe authors have declared no competing interest.