Targeting PTEN Null Tumors via Inhibition of the p110beta Isoform of PI3 Kinase

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DESCRIPTION (provided by applicant): The class IA phosphatidylinositol 3 kinase (PI3K) signaling axis is perhaps the most frequently activated pathway in human cancer. In response to the activation of receptor tyrosine kinases (RTKs), G-protein coupled receptors (GPCRs) or Ras, class IA PI3Ks, consisting of three catalytic isoforms termed p110?, p110? and p110?, are activated to generate the primary intracellular lipid signal, phosphatidylinositol 3,4,5-trisphosphate (PIP3), which is essential for multiple cellular processes. The tumor suppressor PTEN, a lipid phosphatase, dephosphorylates PIP3, thereby antagonizing the actions of PI3K and regulating the PI3K pathway activity. Pathway activation in tumors is most commonly achieved through activating mutations in p110? isoform or via loss of the PTEN tumor suppressor. Importantly, PI3K enzymes are highly suited for pharmacological intervention, making them attractive targets for cancer therapy. In fact, there are a number of PI3K inhibitors from major pharmaceutical companies that have entered clinical trials for cancer treatment, but most of these inhibitors target all p110 isoforms, which may cause side effects arising from the essential roles of PI3K in normal physiology. While isoform specific inhibitors are being further developed, most of which are directed toward p110? (for solid tumors) or p110? (Hematological malignancies). We believe that the drug companies have blundered by failing to develop p110?-specific inhibitors. We and others have recently demonstrated that tumors driven by PTEN loss are specifically dependent of p110? not p110?. The broad goal of this project is to generate p110? -specific inhibitors for use as new, targeted therapeutics in diverse cancers featuring PTEN mutations. To this end we have assembled a team of scientists optimized to achieve this goal. Our team's unique reagents for assessing PI3K signaling, coupled with and our expertise in protein chemistry, X-ray crystallography, medicinal chemistry and animal models, position us to effectively develop p110? inhibitors over a two-year time period for future clinical trials. Our specific goals are to generate cell-based systems and genetic models to determine the role of p110? in tumorigenesis driven by PTEN in different tissue types and to test p110? -specific inhibitors, to purify large amounts of active p110? for enzyme assays and crystallography and to pursue a chemistry campaign to design and evaluate new scaffolds for p110? inhibition and optimize 2 of these scaffolds using both cell and animal models and structural information from a complex of p110? and an inhibitor. PUBLIC HEALTH RELEVANCE: Statement of the relevance of the project to public health: The PTEN tumor suppressor is genetically or epigenetically silenced at high frequency in may types of human cancer. Recent data suggests that tumors driven by PTEN loss are dependent on the activity of a particular isoform of PI3K termed p110?. This project is designed to speed development of p110? inhibitors and hence could have a positive impact on many cancer patients.