) Background: Phosphatidylinositol 3' kinase (PI3K), plays a central role in cellular proliferation, neovascularization, invasiveness, viability, and senescence. PI3K and the MMAC1 (aka PTEN) tumor suppressor gene identified at MDACC phosphorylate and dephosphorylate the same 3'hydroxyl site of the inositol ring of membrane phosphatidylinositols (PtdIns). Preliminary Data: We have demonstrated that the p110 alpha catalytic subunit of PI3K, located at 3q26.3, is frequently genomically amplified in serious epithelial ovarian cancers. P11 alpha mRNA, protein and PI3K enzyme activity are also increased in ovarian cancer cells. MMAC1 is frequently mutated in endometrioid ovarian epithelial cancers. These observations implicate the PI3K signaling pathway in ovarian tumorigenesis. Treatment of cells with amplified PI3K or mutant MMAC1 with specific PI3K inhibitors markedly decreases cell proliferation and leads to apoptosis and anoikis. Further, reintroduction of MMAC1 into cells lacking MMAC1 decreases cell proliferation and inducing apoptosis and anoikis. LY294002 also decreases the growth of human ovarian cancer cells with amplified p110 alpha in nude mice. Rationale: Our preliminary data indicates that the PI3K signaling cascade is critical to ovarian epithelial tumorigenesis and potentially invasion and metastases. Hypothesis: That amplification and mutation of components of the PI3K pathway is critically important for the initiation and progression of ovarian cancer. As a corollary, the PI3K signaling cascade should be evaluated as a marker for prognosis and as a target for novel therapeutics aimed at ovarian cancer.
Specific Aim 1 : What is the impact of amplification, mutation and activation of components of the PI3K pathway on response to therapy or disease outcome? Specific Aim 2: What is the role of amplification of the PI3K pathway on production and action of TGF beta, IL8, VEGF, and ligands for the HER2 family in ovarian cancer? Specific Aim 3: Evaluate the PI3K pathway as a target for therapy in ovarian cancer. Significance: The proposed studies will determine whether assessment of expression or functionality of components of the PI3K pathway will predict patient outcome or drug sensitivity. The proposed studies will also determine the role of the PI3K signaling pathway in the production and action of TGF beta, IL8, VEGF, and ligands for the HER2 family in ovarian cancer studied in other projects in this SPORE. Finally, the proposed studies should determine whether the PI3K signaling pathway is an appropriate target for drug development and identify lead compounds for preclinical and clinical development.
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