2015 Recipient Zeina Kais, PhD

Zeina Kais, PhD

Synthetic Lethality Between CCNE1 Amplification and USP1 Inhibition

Project Summary

High grade serous ovarian cancer (HGSC) accounts for more than 60% of the ovarian cancer deaths and almost no improvement in survival rates has been observed in the past decade. HGSCs exhibiting an increase in the levels of Cyclin E1 protein are even more aggressive tumors that are associated with resistance to the standard chemotherapies used for treatment. Therefore, women diagnosed with this subset of the disease, generally face a poor clinical outcome. In the lab, we have developed a drug that inhibits a protein called USP1. The importance of this drug is that through the inhibition of the USP1 function, it targets two different and unrelated mechanisms that contribute to the chemoresistance and aggressiveness of the disease. First, USP1 inhibition targets the DNA damage repair pathway. Uptake of chemotherapeutic agents causes DNA damage in the cancer cells which in turn activates the DNA repair machinery. In the absence of a functional repair system, the damage accumulates leading to cell death. Ovarian tumors with high Cyclin E1 levels have an intact DNA repair system. Therefore, the cancer cells are capable to detect and repair the damage induced by chemotherapy enabling the cells to survive; and hence the chemoresistance. Since USP1 function is crucial for DNA damage repair, its inhibition would therefore sensitize the cells to the commonly used chemotherapeutic treatments. Our drug has an additional mechanism of killing ovarian cancer cells by promoting the degradation of the ID1 protein. ID1 levels in the cells have been shown by several studies to be high in aggressive ovarian cancers and to correlate with enhanced malignant potential and a more aggressive clinical behavior of the disease. ID1 is thought to contribute to the invasiveness and the growth of the tumors. USP1 functions in stabilizing the ID1 protein levels therefore, USP1 inhibition would lead to ID1 degradation that would eventually lead to a decrease in the tumor growth rate. Therefore, the USP1 inhibitor stands out as a promising therapy for aggressive ovarian tumors with the potential of making an impact on the future management of patients diagnosed with this aggressive subset of the disease. In this study, we will validate the anticancer activity of our drug against ovarian tumors with high cyclin E1 levels both in vitro (using human ovarian cancer cell lines) and in vivo (using mouse models). If successful, our drug can be a highly valuable therapeutic agent for clinical trials in patients with HGSC exhibiting increased Cyclin E1 levels.

Areas of Research:

Bio

Zeina Kais Ph.D. is postdoctoral fellow in the lab of Dr. Alan D’Andrea at Dana Farber Cancer institute in Boston, MA. Dr. Kais earned her B.S. and M.S. from the American University of Beirut (Beirut, Lebanon) and has recently completed her Ph.D. in Molecular Cellular and Developmental Biology under the guidance of Dr. Jeffrey Parvin at the Ohio State University (Columbus, OH). As a graduate student, she was awarded the Presidential Fellowship by the Ohio State University Graduate School in recognition of her outstanding scholarly accomplishments. During her graduate training, her research focused on studying the effect of the different modifiers of the breast/ovarian cancer associated gene 1 (BRCA1) on the function of the protein in the control of centrosome number and DNA damage repair: events that contribute to genetic instability and eventually carcinogenesis. Her current research interests include characterizing and generating pre-clinical data for small molecule inhibitors for the treatment of high grade serous carcinoma (HGSC) with amplified Cyclin E1, an aggressive subtype of ovarian cancer.