The resistance of glioma cells to a number of anti-tumor agents and the highly invasive nature of glioma cells that escape the primary tumor mass are key impediments to the eradication of tumors in glioma patients. In this study, we evaluated the therapeutic efficacy of a novel PI3-kinase/mTOR inhibitor, PI-103, in established glioma lines and primary CD133+ glioma initiating cells and explored the potential of combining PI-103 with stem cell delivered secretable tumor necrosis factor apoptosis inducing ligand (S-TRAIL) both in vitro and in orthotopic mouse models of gliomas. We show that PI-103 inhibits proliferation and invasion, causes G0-G1 arrest in cell cycle, and results in significant attenuation of orthotopic tumor growth in vivo. Establishing co-cultures of neural stem cells (NSCs) and glioma cells, we show that PI-103 augments the response of glioma cells to stem cell delivered S-TRAIL. Using bi-modal optical imaging, we show that when different regimens of systemic PI-103 delivery are combined with NSC-derived S-TRAIL, a significant reduction in tumor volumes is observed compared to PI-103 treatment alone. To our knowledge this is the first study that reveals the anti-tumor effect of PI-103 in intracranial gliomas. Our findings offer a preclinical rationale for application of novel stem cell-based apoptotic therapies to improve treatment of malignant gliomas.