Novel mTORC1 Inhibitors Kill Glioblastoma Stem Cells

Abstract

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.

The Bioinformatics Identification of Potential Protein Glycosylation Genes Associated with a Glioma Stem Cell Signature

“…The mechanistic target of rapamycin (mTORC1), a serine/threonine kinase signaling complex, contributes to the properties of CSCs including GSCs, and it is dysregulated in GBM [40][41][42][43][44]. c-MYC, a well-known stem cell transcription factor, is required for self-renewal and the tumorigenic potential of GSCs [35,45].…”

Unveiling Novel Avenues in mTOR-Targeted Therapeutics: Advancements in Glioblastoma Treatment

“…Targeting the mTOR pathway has been explored as a potential treatment strategy to halt glioblastoma growth and overcome resistance to conventional therapies. The intricate interplay between the mTOR pathway and other signaling cascades in glioblastoma presents a challenging yet critical area of research aimed at developing effective and personalized therapeutic approaches for patients with this aggressive brain cancer [24,31,32].…”

“…In addition, it exhibits complex pharmacokinetics, with variable metabolism and clearance among individuals. Alongside their therapeutic benefits, they can cause various side effects, such as immunosuppression, metabolic disturbances, and impacts on glucose homeostasis [15,17,31]. Despite these limitations, rapalogs have provided valuable insights into targeting the mTOR pathway in glioblastoma and have laid the groundwork for the development of novel mTOR inhibitors [60,61].…”

Biology of IDH mutant cholangiocarcinoma

“…Other reported vulnerabilities in mIDH cancer cells include sensitivity toward inhibition of BCL-2 family proteins in AML cells, attributed to 2HG defects in mitochondria function, [22] to v-src avian sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog kinase inhibitors in iCCA, [153] and mammalian target of rapamycin inhibitors in glioma. [64,154]…”