title: Radiosensitization of Primary Human Glioblastoma Stem-like Cells with Low-Dose AKT Inhibition.
abstract: Glioblastoma (GBM) is the most frequent and lethal brain cancer. The lack of early detection methods, the presence of rapidly growing tumor cells, and the high levels of recurrence due to chemo- and radioresistance make this cancer an extremely difficult disease to treat. Emerging studies have focused on inhibiting AKT activation; here, we demonstrate that in primary GBM tumor samples, full-dose inhibition of AKT activity leads to differential responses among samples in the context of cell death and self-renewal, reinforcing the notion that GBM is a heterogeneous disease. In contrast, low-dose AKT inhibition when combined with fractionation of radiation doses leads to a significant apoptosis-mediated cell death of primary patient-derived GBM cells. Therefore, low-dose-targeted therapies might be better for radiosensitization of primary GBM cells and further allow for reducing the clinical toxicities often associated with targeting the AKT/PI3K/mTOR pathway. This work emphasizes the discrepancies between cell lines and primary tumors in drug testing, and indicates that there are salient differences between patients, highlighting the need for personalized medicine in treating high-grade glioma.
authors.affiliation: Department of Pharmacology, RBHS-Robert Wood Johnson Medical School, Graduate School of Biomedical Sciences, Rutgers University, New Brunswick, New Jersey.
authors.forename: Monal
authors.initials: M
authors.lastname: Mehta
authors.affiliation: Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, New Jersey. Department of Radiation Oncology, Rutgers University, New Brunswick, New Jersey.
authors.forename: Atif
authors.initials: A
authors.lastname: Khan
authors.affiliation: Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, New Jersey. Department of Neurosurgery, Rutgers University, New Brunswick, New Jersey.
authors.forename: Shabbar
authors.initials: S
authors.lastname: Danish
authors.affiliation: Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, New Jersey. Department of Radiation Oncology, Rutgers University, New Brunswick, New Jersey.
authors.forename: Bruce G
authors.initials: BG
authors.lastname: Haffty
authors.affiliation: Department of Pharmacology, RBHS-Robert Wood Johnson Medical School, Graduate School of Biomedical Sciences, Rutgers University, New Brunswick, New Jersey. Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick, New Jersey. Department of Medicine, RBHS-Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey. sabaawhe@cinj.rutgers.edu.
authors.forename: Hatem E
authors.initials: HE
authors.lastname: Sabaawy
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001562:Benzimidazoles / Q000494:pharmacology*; D001932:Brain Neoplasms; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000528:radiation effects; D057285:Precision Medicine; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011810:Quinoxalines / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: C532657:1,3-dihydro-1-(1-((4-(6-phenyl-1H-imidazo(4,5-g)quinoxalin-7-yl)phenyl)methyl)-4-piperidinyl)-2H-benzimidazol-2-one; D001562:Benzimidazoles; D011810:Quinoxalines; D011838:Radiation-Sensitizing Agents; D051057:Proto-Oncogene Proteins c-akt