The aim of this proposal is to identify and validate biomarkers that will, for the first time, enable individualization of therapy in ovarian cancer. This proposal will thus include the execution of an innovative phase II clinical trial that will facilitate the validation of novel biomarkers that predict the clinical efficacy of targeted therapies in individual women with ovarian cancer. We will target two biologic processes that we and others have established as playing critical roles in the pathogenesis of epithelial ovarian cancer: (i) activation of the phosphatidylinositide-3-kinase (PISK/AKT/mTOR) pathway ('PISKness'), and (ii) deficient BRCA1/2-mediated homologous recombination (HR) ('BRCAness'). This proposal will build on the successful phase I trial targeting the PISK signaling pathway in ovarian cancer thay we executed in the previous SPORE funding period. It will also build on our new data indicating that somatic mutations and loss of BRCA1 and BRCA2 function are significantly more common than previously thought in ovarian cancer and should predict sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) that exhibit synthetic lethality with BRCA1/2 dysfunction. This proposal will bring together: 1. the SouthWest Oncology Group (SWOG) to facilitate execution of the phase II trial, 2. Astra Zeneca to provide access to the novel therapies olaparib (PARPi) and AZD8055 (PISK pathway inhibitor), and 3. Myriad Genetics, Inc.
The specific aims are:
Aim 1 : A. To determine whether 'PISKness'predicts responsiveness to PISK pathway inhibitors in cell lines and ovarian cancer xenografts. B. To determine whether 'PISKness'predicts outcome in ovarian cancer patients treated with surgery and platinum/paclitaxel-based chemotherapy.
Aim 2; A. To determine whether 'BRCAness'predicts responsiveness to PARP inhibitors in cell lines and ovarian cancer xenografts. B. To determine whether """"""""BRCAness"""""""" predicts outcome in ovarian cancer patients treated with surgery and platinum/paclitaxel-based chemotherapy.
Aim S;To determine whether 'PISKness'and 'BRCAness'predict response to targeting the PISK/AKT/mTOR pathway and PARP, respectively, in a phase II ovarian cancer clinical trial.
The successful execution of this study wiil contribute to: 1) the implementation of novel therapies with clinical utility, and 2) progress towards individualization of treatment for women with ovarian cancer. As a result, we expect that the successful execution of this research proposal will lead to improved therapy and outcomes for w/omen with ovarian cancer as well as define paradigms and trial designs that can be applied broadly to increase the rate of successful implementation of targeted therapy in ovarian cancer.
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