Abstract 2506: Palomid 529, a PI3K/Akt/mTOR dual TORC1/2 inhibitor, is a radiosensitizer with effect in both subcutaneous and orthotopic U251 glioblastoma tumor xenograft models

Abstract

Abstract Palomid 529 (P529) is a small molecule drug created through three generations of computational design. P529 is an anti-tumor agent able to target and inhibit the PI3K/Akt/mTOR signal transduction pathway, specifically as an allosteric dual TORC1/TORC2 inhibitor causing the dissociation of the TORC complexes. Furthermore, P529 has been shown to broadly inhibit cell lines of the NCI 60 cell screen, inhibit HIF-1α, and show tumor growth delay in murine tumor xenograft models. P529 is able to cross the blood-brain barrier and show little or no effect of two transporters (P-gp and Bcrp1) in brain uptake of P529. Here we show that P529 has a more than additive radiation sensitizing activity inhibiting tumor growth in U251 glioblastoma tumor xenograft models both subcutaneous and orthotopic. P529 was administered in a dose-dependent manner at 25, 50 and 95 mg/kg oral dosing every day for 5 days with 4 Gy radiation given on day three. Tumor xenografts in both subcutaneous and orthotopic models were evaluated daily for tumor size or survival respectively up to 40 days post tumor implantation. P529 treatment alone showed marked decrease in tumor growth (subcutaneous) and increase in survival (orthotopic). With addition of radiation, there was a synergistic increase in activity of P529 on the inhibition of U251 tumor growth and survival. All in all, work described here provides evidence that P529 has activity as a radiosensitizer in murine models of glioblastoma and the possibility of efficacious activity in treatment of human patients under a novel mechanism of inhibition of the PI3K/Akt/mTOR pathway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2506.