Grant: Project Grant

Ovarian cancer is the 5th most common cause of cancer in women, but it is the most lethal gynecological cancer. Of the five types of ovarian cancer, tubo-ovarian high-grade serous carcinoma (HGSC) is the most common and lethal form. Although patients initially respond to chemotherapy, ~75% relapse within 1.5 years and ultimately succumb with drug-resistant disease. The development of new, anti-cancer treatments is a significant research challenge; however, recent efforts suggest that exploiting the mutated genes causing cancer may hold tremendous clinical potential. Accordingly, greater insight into the mutated genes and abnormal pathways driving HGSC development is needed so that new treatment strategies and drugs can be developed that exploit them. Mutations in specific genes cause genome instability, which is an early step in the development of most HGSCs. Genome instability often leads to abnormal chromosome (structural elements containing genes/DNA) numbers that promotes cancer development and progression. We believe that to create new, effective chemotherapies requires a deeper understanding of the abnormal genes and pathways causing HGSC. In this regard, emerging data have identified a gene (SKP2) that we suspect is a driver of HGSC. Data from patient tumor samples shows that SKP2 is altered in ~10% of all HGSCs. Moreover, our pilot studies show that reduced SKP2 expression causes genome instability and changes in chromosome numbers, which collectively suggest that abnormal expression may play a key role in HGSC development. To explore this possibility, we will generate and use clinically relevant models and leading-edge genetic and cell biology techniques to gain new insight into SKP2 and its role in HGSC development. We will exploit this information to identify new drug targets and lead chemotherapeutics that we will test in pre-clinical studies to ideally and ultimately deliver new therapeutic options to individuals diagnosed with HGSC.