Molecular alterations characteristic of glioblastoma include the amplification of EGFR and the loss of thePTEN tumor suppressor, which lead to the constitutive activation of the PI3K/Akt pathway and provides therationale for our focus in this Project on a unique PI3K inhibitor, PX-866 (ProIX). This wortmannin analogoffers three key improvements: 1) it is biologically stable; 2) it is a more potent inhibitor of the p110-asubunit of PI3K and 3) it is a weaker inhibitor of p110-p, and so shows much reduced dose limiting ontargettoxicity common to all PI3K inhibitors. We plan to test the hypothesis that the PI3K inhibitor PX-866 is an effective therapy for glioma by evaluating it in preclinical models and in the clinic in early phaseclinical trials for glioblastoma. However, the limited success of signal transduction inhibitors used as singleagents, which is most likely due to compensatory or collateral pathways, is a strong rationale for exploringcombination therapies. Some combinations can be suggested on the basis of current knowledge ofsignaling pathways, and we propose to test the most compelling in our models and the clinic. At the sametime we plan to identify additional molecular target(s) or pathway(s) that would, once they are blocked byanother drug, confer synergy to a PI3K inhibitor, based on siRNA synthetic lethality screening. Togetherthese efforts will test the hypothesis that combination therapies based on PI3K inhibitors areeffective in the treatment of glioma.
Our Specific Aims are 1) To study PX-866 and rational combinationsin improved preclinical culture and animal models of glioma, using xenografts of human glioma cells thatretain the molecular hallmarks of the parental tumors and on brain cancer stem cells. Rationalcombinations include PX-866 and the small molecule drugs Tarceva, Sorafenib and rapamycin/RADOOl aswell as the standard of care - radiation and temozolomide; 2) To initiate clinical trials of PX-866 and rationalcombinations, based on the data obtained in Aim 1; and 3) To identify novel synergistic targets for rationaldrug combinations with PX-866 using siRNA synthetic lethality screening. By completing these Aims we willpursue, in parallel, the clinical deployment of a promising PI3K inhibitor and the development ofcombination therapies based on it. Both rational (Aim 1) and newly discovered (Aim 3) co-targets/therapieswill be developed, allowing both near-term and mid-term combination therapies to follow the individual leadcompound (Aim 2) into clinical evaluation. Therefore this project emphasizes the translational dimension ofour signal transduction research program with the hope of accelerating promising new treatment to thebedside.
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