Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor and predicts a poor prognosis despite current treatment modalities. Aberrant activation of the phosphatidyl-inositol-3-kinase (PI3K) pathway is observed in nearly 90% of GBMs making the downstream effector, mammalian target of rapamycin (mTOR), a potential drug target. mTOR is a serine/threonine kinase that regulates cell growth, proliferation, survival, protein translation and metabolism by integrating signals received from the PI3 K/Akt signaling pathway. The allosteric mTOR inhibitor rapamycin has failed in the clinic as a treatment for GBM patients. Therefore, in the current study, we examined the potential benefit of MLN0128, a novel potent mTOR ATP competitive inhibitor, as a therapeutic strategy for GBM. We assessed in vitro antiproliferative activity of MLN0128 in a panel of GBM tumor and stem cell lines. MLN0128 significantly inhibited cell proliferation of both GBM tumor and stem cells. It decreased the phosphorylation of mTOR, Akt, S6, 4E-BP1, and NDRG1, inhibiting both mTORC1 and mTORC2 signaling in GBM. Thus, MLN0128 appears to be superior in blocking mTORC1/2 signaling in contrast to rapamycin. It inhibited migration and invasion of GBM cells in a matrigel coated chamber assay. On clonogenic survival assay MLN0128 decreased GBM cell survival and increased radiosensitivity. To investigate the mechanism of radiosensitization, the induction and repair of DNA double-strand breaks were evaluated by γH2AX foci formation. MLN0128 exposure significantly delayed the dispersal of radiation induced γH2AX foci formation in both tumor and stem cells. These results indicate that MLN0128 enhances tumor cell radiosensitivity by inhibiting DNA repair. Next we combined MLN0128 with temozolomide (TMZ), a FDA approved radiosensitizer for GBM therapy. Although, we did not observe any synergy in inhibition, addition of TMZ did not adversely affect MLN0128 inhibitory effects. These findings support the rationale for clinical testing of MLN0128 in patients with GBM to provide insight towards optimizing therapeutic efficacy of mTOR kinase inhibitors with standard care.
Note: This abstract was not presented at the meeting.
Citation Format: Anita T. Tandle, Philip Tofilon, Kevin Camphausen. mTOR kinase inhibition enhances radiosensitivity in glioblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4906. doi:10.1158/1538-7445.AM2014-4906