Novel mTORC1 Inhibitors Kill Glioblastoma Stem Cells.
Jose A SandovalAlexey TomilovSandipan DattaSonia AllenRobert O'DonnellThomas SearsKevin WoolardDmytro KovalskyyJames M AngelastroGino CortopassiPublished in: Pharmaceuticals (Basel, Switzerland) (2020)
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.
Keyphrases
- wild type
- stem cells
- cell proliferation
- endothelial cells
- low grade
- newly diagnosed
- clinical trial
- healthcare
- palliative care
- blood brain barrier
- dna binding
- structure activity relationship
- white matter
- binding protein
- induced pluripotent stem cells
- quality improvement
- resting state
- oxidative stress
- cell therapy
- multiple sclerosis
- big data
- chronic pain
- brain injury
- machine learning
- mass spectrometry
- high grade
- functional connectivity
- atomic force microscopy
- affordable care act
- smoking cessation
- double blind