Mutations in the DNA repair gene Brca1 and Brca2 that are passed along from parents to their children are a major cause of ovarian cancers in families. The Brca1 and Brca2 mutation can also be seen in in non-familial ovarian cancer (BRCA-ness phenotype). One way to fight ovarian cancer is to use PARP inhibitors so that ovarian cancer cells are killed when DNA repair defect occurs in BRCA-ness ovarian cancer. Another protein that has been found to help repair DNA damage is called, 53BP1, and if ovarian cancer cells are resistant to PARP inhibitors then it may be because 53BP1 is helping to restore DNA repair function in tumors with BRCA-ness. Exactly how these two proteins interact when repairing DNA double-strand breakage is not fully understood. Thus, it is important to understand: 1) how 53BP1 competes with BRCA1 function to allow ovarian cancer cells resistant to PARP inhibitors; and 2) how to effectively treat ovarian cancer tumors that are BRCA-ness and also defective in 53BP1 expression. Understanding these two points will allow us to pinpoint what makes the ovarian susceptible to cancer development and identify what other mutations may be making BRCA-ness ovarian tumors resistant to therapies like PARP inhibitors, ultimately leading to better cancer treatments for BRCA-ness ovarian cancer patients.
Several clinical trials are currently ongoing for PARP inhibitors in ovarian cancer patients; therefore, understanding how ovarian cancer cells are escaping the effects of PARP inhibitors will allow us to develop better treatment strategies, especially in patients who have BRCA-ness ovarian cancer. The primary innovation of this proposal is to determine synthetic lethality with DNA repair pathways network is exploited to overcome PARPi-resistant ovarian cancer. This could have an immediate impact on patients given that the PARP inhibitors are in clinical trials now.
Building on these important scientific discoveries, our long-term goals is aimed at applying the acquired knowledge from our basic cancer research to the development of specific, effective, rationally designed therapies that targeted DNA damage signaling pathways for BRCA-ness patients, which aligns well with the mission of Ovarian Cancer Research Fund, and eventually to reduce the incidence and mortality of ovarian cancer within the next decade.