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

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.

Dual mTORC1 and mTORC2 inhibitor Palomid 529 penetrates the Blood–Brain Barrier without restriction by ABCB1 and ABCG2

“…Although the PI3K‐mTOR signaling pathway is very frequently activated in this disease, it is not very likely that a single agent directed against this pathway by itself can exert a potent anti‐proliferative effect. In this respect, however, Palomid 529 has been shown to synergize with radiation in experimental models including orthotopic gliomas . Importantly, in this study, we demonstrate that pharmacologically active levels of Palomid 529 can be delivered throughout the brain, which is important as this drug is being considered for clinical evaluation in high‐grade glioma.…”

“…In this respect, however, Palomid 529 has been shown to synergize with radiation in experimental models including orthotopic gliomas. 8,9 Importantly, in this study, we demonstrate that pharmacologically active levels of Palomid 529 can be delivered throughout the brain, which is important as this drug is being considered for clinical evaluation in high-grade glioma.…”

“…In vivo studies showed that Palomid 529 reduced angiogenesis, vascular permeability and tumor growth. 7 Moreover, it has been reported that Palomid 529 enhances the anti-proliferative effect of radiotherapy in glioblastoma in an orthotopic model 8 as well as in prostate tumor models, 9 and more recently, this dual mTORC1 and mTORC2 inhibitor has exhibited its effect to sensitize the chemotherapy in hormone refractory prostate tumors. 10 The brain is a pharmacological sanctuary site due to the inability of many drugs to cross the blood-brain barrier (BBB) in a therapeutic meaningful dose.…”

Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario

“…Palomid 529 likewise inhibits both VEGF-driven and bFGF-driven endothelial cell proliferation [ 758 ]. Due to its potential to penetrate the BBB without restriction by the ABCB1 and ABCG2 efflux transporters, the anti-glioma effects of this drug have been investigated [ 759 , 760 , 761 ]. In childhood cancer, a single report proved a potent inhibition of viability, cell cycle progression and proliferation of the OS cell line U2OS [ 762 ].…”

Targeting core (mutated) pathways of high-grade gliomas: challenges of intrinsic resistance and drug efflux

“…In vivo studies demonstrated that Palomid 529 reduced angiogenesis, vascular permeability and tumor growth [80]. Moreover, Palomid 529 was shown to enhance the antiproliferative effect of radiotherapy in GBM in an orthotopic model [81], as well as in prostate tumor models [82]. Another way to interrupt the mTORC2-PI3K positive-feedback loop is by combined inhibition of mTORC1 and PI3K.…”