Our previous work was focused on ?proof of concept? experiments to establish the clinical utility of pan PI-3 kinase inhibitors in preclinical models for glioma therapeutics and to evaluate the mechanisms for PTEN?s regulation of glioma progression including elements of angiogenesis and downstream pharmacodynamic targets for PI-3 kinase action. The previous work involved the study of a well-characterized pan PI-3 kinase inhibitor, LY294002 in glioma models. The LY294002 compound, for a number reasons (discussed below) is not a viable drug candidate for clinical development. In our competitive renewal we will focus on our current ongoing preclinical development of a novel small molecule inhibitor of PI-3 kinase co-developed in our laboratory (in collaboration with Semafore pharmaceuticals) for glioma therapeutics. This inhibitor is a vascular RGDS targeted prodrug derivative of LY294002 and is termed SF1126. Below we present our preliminary data which supports our proposal to further evaluate this targeted pan PI-3 kinase inhibitor in preclinical models for malignant glioma. Hypothesis: A pan PI-3 kinase inhibitor (SF1126) will attenuate the growth of malignant glial tumors in nude mice via its control over a number of important signaling pathways including the HIF-1a-VEGF signaling axis. A pan PI-3 kinase inhibitor will display anti-glioma and antiangiogenic activity in vivo. Our goal is to perform formal PK-PD modeling of SF1126 as relates to PK and PD parameters, PTEN status of tumor and effects on angiogenesis and important downstream biomarkers. Below we show a schematic which outlines the ?intercept concept? the rationale behind targeting all PI-3 kinases as compared to the inhibition of a single cell surface receptor or tyrosine kinase. The primary goal our previous grant proposal, CA94233 was to: ?determine the utility of pan PI-3 kinase inhibitor in preclinical models for glioma therapeutics?. Herein, we present the development of a clinically viable pan PI-3 kinase inhibitor prodrug, SF1126 and we embark on a careful characterization of this agent in preclinical glioma models. The overarching goal is to prepare this agent for a Phase I clinical trial in glioma patients.
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