Ovarian carcinoma is a heterogeneous disease composed of different histologic subtypes with distinct clinical, pathologic and molecular genetic features. We will largely focus on one type, high-grade serous carcinoma, because it is the most common type and accounts for the vast majority of deaths. The NCI Gynecologic Cancers Progress Review Group has listed several high-impact priorities for reducing the burden of ovarian cancer, including identification of markers of risk and new targets for prevention, tests for early detection, and new approaches to treatment. The research program in this SPORE application specifically addresses these high priority issues and is based on the discoveries made by the ovarian cancer research team at our institution over the past decade. The specific aims of this SPORE are as follows:

    1. Apply PapGene test for early ovarian cancer detection using routinely collected liquid based cervical cytology specimens.
    2. Modulate the ovarian tumor microenvironment with listeria-based vaccination.
    3. Introduce epigenetic therapy to augment immune signaling and sensitize ovarian cancer to immune checkpoint inhibitors.
    4. Explore the potential of SYK inhibitors to sensitize ovarian cancer to the anti-tumor effects of paclitaxel.

In contrast to the conventional empirical approaches to the management of ovarian cancer, all the projects in this program are based on better understanding of the basic tumor biology and the tumor microenvironment of ovarian cancer, and therefore will have a very substantial impact on the field. Specifically, early detection of high-grade serous carcinoma will allow for more effective treatment, as it will be directed at small tumors that have not undergone the extensive genetic intratumoral heterogeneity that leads to drug resistance. On the other hand, evaluating novel therapeutic approaches for advanced stage ovarian cancer will open an entirely new avenue of cancer treatment for this devastating disease. Thus, this SPORE is expected to have a major impact on clinical outcome in ovarian cancer patients and improve overall survival.