My career goal is to understand the role of cell senescence and Wnt signaling in regulating ovarian cancer initiation and progression. In the long term, I hope to be able to exploit the possibility to develop novel therapeutic strategies for ovarian cancer through driving ovarian cancer cells to undergo senescence by targeting Wnt signaling. The ovarian cancer academy award will not only provide pivotal funding support to allow me to establish an independent program at the forefront of ovarian cancer research, but also provide a unique virtual platform to network with other early career investigators and receive critical mentoring from other mentors and the academy dean. If awarded, I will be fully committed to the virtual academy meetings and regular communication with other members of the academy to facilitate the process in achieving my career goal to become an independent and highly productive ovarian cancer researcher.

Ovarian cancer is the eighth most common cancer in women and ranks first as the cause of death for gynecological cancers. Approximately 22,430 women in the United States are diagnosed with ovarian cancer annually, and 15,300 women die of this disease (www.cancer.org). Obviously, there is an urgent need to develop novel treatment methods for ovarian cancer. To do this, we must better understand key events associated with ovarian cancer development.

Transformation of normal human cells into cancerous cells requires multiple deleterious genetic alterations. In order to combat cancer, a normal cell's typical response to a tumor-promoting genetic alteration is irreversible growth arrest, consequently preventing the normal human cell from progressing towards becoming a cancer cell. This process is termed oncogene-induced senescence (i.e., a process induced by evolution into an organism's genetic makeup so that it may live to its healthiest until its reproductive age and die slowly and gradually thereafter). When this process fails, those cells containing tumor-promoting genetic alterations can grow without control and become a tumor. The potential use of cellular senescence for cancer therapy would rely on reactivation of this process in cancer cells. Consistent with this, in mouse models, reactivation of cellular senescence drives irreversible growth arrest of cancer cells, and consequently leads to tumor regression, suggesting that cellular senescence could be used for cancer therapy.

We have previously discovered a pathway that opposes the beneficial process of oncogene-induced senescence. This pathway is referred to as the canonical Wnt signaling pathway. Our preliminary studies established that ovarian cancer causing genetic alterations induce senescence of ovarian epithelial cells. In addition, we have evidence to suggest that canonical Wnt signaling pathway is inappropriately activated in ovarian cancer cells, and inhibition of the signaling suppresses the growth of ovarian cancer cells. Therefore, we hypothesize that canonical Wnt signaling pathway contributes to the development of this disease through bypassing oncogene-induced senescence. In the proposed studies, we will rigorously test this hypothesis. Using a series of complimentary methods, we will determine whether inhibition of canonical Wnt signaling induces senescence of ovarian cancer cells and whether activation of canonical Wnt signaling contributes to ovarian cancer development through overcoming oncogene-induced senescence. The proposed studies may lead to development of strategies for ovarian cancer treatment using reactivation of cellular senescence as a novel mechanism by targeting ovarian cancer promoting canonical Wnt signaling.

The completion of the proposed studies will likely generate enough preliminary data to compete successfully for additional funding from other federal agencies (such as National Institute of Health or American Cancer Society). In addition, I anticipate that the proposed studies will also generate ovarian cancer-focused publications in professional peer-reviewed journals.

In summary, the ovarian cancer academy award will be critically important in helping me establish an independent ovarian cancer research program and sustain a productive career at the forefront of ovarian cancer research.