One in every four deaths in the US is due to cancer. The overall cancer drug market exceeds $2 billion in the USA. There is significant need to identify novel and selective small molecule-based cancer therapies. This proposal seeks to undertake preclinical evaluation of a novel class of inhibitors of phosphatidyl inositol 3-kinase for the eventual use of an agent as a therapy against solid and hematologic cancers. There is strong evidence for the following: 1) The phosphatidylinositol-3-kinase (PI-3K)/Akt (protein kinase B) pathway is a survival signaling pathway that is activated in many types of human cancer. 2) PTEN, a lipid phosphatase that attenuates PI-3K signaling by dephosphorylating PI-3-phosphates, is lost in a large number of human tumors leading to constitutive activation of PI-3K/Akt survival signaling pathway. 3) ProIX Pharmaceuticals has identified several novel viridin analogues that show potent inhibition of PI-3K, with better biological stability and without the severe liver toxicity of wortmannin. 4) These viridin analogues show good single agent antitumor activity against a number of human tumor xenografts in immunodeficient scid mice and potentiate the activity of both currently used cytotoxic and molecularly targeted (EGFR kinase) chemotherapeutic drugs. From this group of agents, ProIX has selected a drug lead and is undertaking more extensive pre-clinical development of this agent. The objectives of this Phase I study to be conducted by ProIX Pharmaceuticals are to gain an understanding of the biological activity of the lead agent, PX-866. Specifically it is intended 1) to determine major metabolites of PX-866 in mice; 2) to develop surrogate molecular endpoint assays, and relate these endpoints to target inhibition in tumors; and 3) to define the role of PTEN in the potentiation of the response to EGFR kinase inhibitors by PX-866. The results of this application will lead to more extensive pre-clinical development of the agent, progressing it toward an IND application and a Phase I clinical trial. ProIX has the exclusive license to develop these agents as an anticancer drug.
