Abstract
The resistance of glioma cells to a number of antitumor 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 G(0)-G(1) arrest in cell cycle, and results in significant attenuation of orthotopic tumor growth in vivo. Establishing cocultures of neural stem cells (NSC) and glioma cells, we show that PI-103 augments the response of glioma cells to stem cell-delivered S-TRAIL. Using bimodal 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 with PI-103 treatment alone. To our knowledge, this is the first study that reveals the antitumor effect of PI-103 in intracranial gliomas. Our findings offer a preclinical rationale for application of mechanism-based systemically delivered antiproliferative agents and novel stem cell-based proapoptotic therapies to improve treatment of malignant gliomas.
Highlights
Glioblastoma multiforme (GBM) is the most common and aggressive form of malignant brain tumors
We further analyzed the effects of PI-103 on a selected glioma line, Gli36-EvIII, and showed that PI-103 resulted in a proliferative arrest in the cell cycle with a proportional increase in G0–G1, a decrease in the S phase and no change in the G2 phases of cell cycle (Fig. 1C)
We demonstrate the effect of a dual PI3 kinase (PI3K)/ mammalian target of rapamycin (mTOR) inhibitor, PI-103, in a panel of established and primary invasive glioma cell lines and provide evidence of the antitumor effects of systemically delivered PI-103 in intracranial glioma models
Summary
Glioblastoma multiforme (GBM) is the most common and aggressive form of malignant brain tumors. Despite the advances in the understanding of glioma biology, GBMs remain very difficult to eradicate and the median survival after diagnosis is still less than 12 months [1]. The inherent or acquired resistance of tumor cells to a number of antitumor agents and the highly invasive nature of tumor cells that escape the primary tumor mass and subsequently cause recurrence [2, 3] are among the major obstacles in finding an optimal cure for GBMs. the lack of efficient delivery of promising anti-GBM agents contribute to therapeutic failure [4]. A number of genetic alterations are implicated in GBM progression, contributing to high proliferation, resistance to apoptosis, and extreme invasion capabilities of GBM tumors [5].
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