(Overall) The Overall section of this Ovarian Cancer SPORE application describes the Background, Specific Aims, Innovation, and Research Plan of the three projects and four cores. We emphasize intra- SPORE collaborations and development of clinical trials with companion biomarkers. Through this SPORE application, we have tried to address several of the most urgent questions in ovarian cancer therapy. First, PARP inhibitors are a new and essential feature of high grade serous ovarian cancer (HGSC) therapy, but many patients eventually have cancer progression on these agents. Accordingly, in Project 1, we have designed clinical trials with drug combinations and correlative studies which will allow us to systematically extend the use of PARP inhibitors. Second, we recognize the emerging impact of immunotherapy on solid tumor treatment. Thus, in Project 2, we have designed a novel vaccine trial for ovarian cancer patients. Third, HGSC patients with primary refractory disease or those patients with recurrence whose cancer harbor underlying RAS mutations such as low grade serous or mucinous cancers pose a particularly difficult clinical problem. Accordingly, in Project 3, we will explore novel non-platinum drug combinations, such as the combination of a BCL inhibitor and a MEK inhibitor, and will examine predictive biomarkers and tumor responses evident in the extracellular activity.
The Specific Aims of this DF/HCC ovarian cancer SPORE are as follows:
Aim 1 (Project 1): ATR inhibitor-mediated reversal of PARP inhibitor resistance in high-grade serous ovarian cancer (HGSOC);
Aim 2 (Project 2): Combined personal neoantigen-targeting cancer vaccines with immune checkpoint blockade for ovarian cancer;
Aim 3 (Project 3): Evaluation of the Efficacy of Trametinib + Navitoclax in recurrent ovarian carcinoma.
(Overall) This is an Ovarian Cancer SPORE resubmission (A1) application, submitted by a team of investigators from the Dana-Farber/Harvard Cancer Center (DF/HCC). The SPORE contains three projects and four cores, which are highly interactive. It also contains a Developmental Research Program (DRP) and a Career Enhancement Program (CEP). The program is focused on the broadest and most urgent questions in ovarian cancer therapy, including novel drug combinations, and immunotherapy.