Activation of AKT promotes tumor cell survival, proliferation and invasiveness, suggesting that AKT may play a central role in tumorigenesis and therapeutic response. AKT is frequently activated in ovarian cancer and may occur early in tumor progression. Rapamycin targets AKT signaling via inhibition of mTOR, leading to G1 arrest in tumor cells with activated AKT. Fatty acid synthase (FAS) is often overexpressed in ovarian carcinomas, and its expression is regulated in part by AKT signaling. Enzymatic inhibition of FAS by specific pharmacologic agents induces apoptosis in tumor cells. Collectively, these data suggest that mTOR and FAS are promising targets for the treatment of ovarian cancer patients. The long-term objective of this proposal is to determine if mTOR or FAS inhibition by specific pharmacologic agents can be therapeutically efficacious in ovarian carcinomas, and whether response is dependent on the AKT status of a given tumor.
The specific aims are"""""""" 1) Determine whether AKT activation and genomic imbalances occur early in the progression of human ovarian cancer. Immunostaining will be performed on putative preneoplastic ovarian lesions to determine if activation of AKT is an early event in ovarian tumorigenesis. To place AKT activation in the context of a model of ovarian tumor progression, array-CGH, an invaluable new tool that permits high-resolution analysis of genomic imbalances, will also be used to identify early somatic genetic changes in these same specimens. 2) Identify potential synergy between FAS inhibition or mTOR inhibition and various chemotherapeutic agents in ovarian cancer cell lines with or without constitutive activation of AKT. 3) Determine whether pharmacologic inhibition of AKT pathways can repress ovarian tumor formation. As a chemotherapeutic strategy, xenograft models of human ovarian cancer will be used to assay anti-tumorigenic effects of mTOR and FAS inhibitors. As a chemoprevention strategy, a transgenic ovarian cancer model expressing active AKT will be used to determine if rapamycin can inhibit or delay tumor formation. 4) Conduct a phase II trial of an mTOR inhibitor in the treatment of ovarian cancer. Overall, these studies will yield important insights regarding the value of AKT as a biomarker for predicting ovarian cancer development, progression and drug sensitivity and will ascertain whether AKT pathway inhibition can serve as an effective chemopreventive and/or chemotherapeutic strategy in ovarian cancer.
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