Ovarian cancer remains the most fatal gynecological cancer. The major cause for continuous low survival rates is the challenge of early detection. As long as this challenge is not addressed, women depend on second or third line of treatment for survival.
ATR (Ataxia Telangiectasia and Rad3-related) is a protein kinase that participates in DNA damage and replication stress response and plays a central role in the maintenance of genome integrity. Tumors with high oncogenic stress are particularly sensitive to the loss of ATR because of their elevated replication stress due to uncontrolled cell proliferation. Therefore, targeting ATR is an attractive option in exploiting tumor-associated replication stress. Currently, several specific ATR inhibitors (ATRi) are in stage I/II clinical trials as mono and combination therapy.
To maximize the effectiveness of ATRi treatment, tumors associated with high replication stress need to be identified, which most ovarian cancers have. Thus, ovarian cancers could potentially be treated with ATRi. However, a comprehensive list of biomarkers to predict the sensitivity to ATRi is still missing. Moreover, effectiveness of these possible biomarkers still needs to be proven clinically.
Here, we propose to investigate the effects of ATRi on different ovarian cancer cells characterized as high-grade serous ovarian, ovarian clear cell and ovarian endometrioid cancer cell lines in attempts to establish mechanisms of action and mechanisms of resistance to ATR inhibition.
In preliminary experiments, we established that new and unbiased approaches are necessary to identify factors that have a reliable impact on predicting the response to ATRi treatment. Therefore, we will perform functional proteomic analysis and genome-wide CRISPR screens of ATRi sensitive and resistant cell lines.
Furthermore, we will elucidate phenotypes and mechanisms of ATRi resistance using in vitro generated cell lines resistant to ATR inhibition. With this approach we will be able to compare relevant factors in resistant cell lines directly to their sensitive parental cell lines, and thus circumvent the difficulty of comparing cell lines of different origin.
Lastly, we will validate biomarkers, mechanisms of action and resistance to ATR inhibition in vivo.
In summary, our ovarian cancer studies have one goal, bringing ATRi to the clinic. We hope that our results will identify key ovarian cancer-specific biomarkers that allow us to increase the success rate of ATRi-based therapy.