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 late preclinical development of a novel inhibitor of phosphatidyl inositol 3-kinase for the eventual use of the agent, PX-866, 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) ProlX 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) One of these viridin analogues shows good single agent antitumor activity against a number of human tumor xenografts in immunodeficient scid mice and potentiates the activity of both currently used cytotoxic and molecularly targeted (EGFR kinase) chemotherapeutic drugs. ProlX has selected PX-866 as the lead PI-3K inhibitor to develop as a novel cancer therapy. The objectives of this Phase 2 application to be conducted by ProlX Pharmaceuticals, are to further advance PX-866 toward a clinical trial by completing Exploratory IND enabling safety, formulation and biological endpoint studies. Specifically it is intended 1) to develop intravenous and oral formulations of PX-866 with corresponding stability studies; 2) to compare and initiate validation of surrogate molecular endpoint assays; and 3) to evaluate the safety of PX-866 in rat and dog species to identify a dose for an ensuing Phase 0 clinical trial. The results of this application will lead to the submission of an Exploratory IND application allowing the agent to be evaluated in the clinic through the newly developed guidelines for clinical pharmacokinetic studies. ProlX has the exclusive license to develop PX-866 agent as an anticancer drug. ? ? ?
