High-grade serous ovarian cancer (HGSOC) accounts for more than 70% of all ovarian cancer deaths. Most women with HGSOC are diagnosed when the disease is at an advanced, and therefore less curable, stage. PARP inhibitors are the first FDA-approved biological agent for the treatment of ovarian cancer with the specific feature-homologous recombination deficiency (HRD). PARP inhibitors have shown great promise in the treatment for HGSOC patients.
Unfortunately, resistance to PARP inhibitors has proved to be a major challenge in the clinic. There are two types of treatment resistance to PARP inhibition in ovarian cancer: acquired resistance and initial resistance. 1) acquired resistance: HRD is found in approximately 50% of HGSOC patients, these patients initially response to PARP inhibitor therapy, however, majority of them develop resistance during treatment. 2) initial resistance: the other 50% of HGSOC patients without HRD feature do not response to PARP inhibitor treatment. This necessitates development of new treatment options to overcome both initial and acquired PARP inhibitor resistance in the clinic.
Recently, we generated ovarian cancer mouse models and reported that PARP inhibitors can induce a strong immune response and could be used in combination with immunotherapy for the treatment of HGSOC patients with typical HRD features-BRCA gene mutation. These results are further supported by the recent clinical success. We treated our BRCA1-deficient ovarian cancer mouse model long term with PARP inhibitors, which resulted in tumors resistant to PARP inhibition. By using these tumors with acquired resistance to PARP inhibition, we identified a potential PARP inhibitor resistance mechanism emanating from and dependent on the immune cells in the environment surrounding the tumor. In the proposed study, we will elucidate the new resistance mechanism of PARP inhibition and develop new treatment options for ovarian cancer patients with acquired resistance to PARP inhibition. Moreover, we also generated a mouse model with overexpression of Cyclin E1 gene which is frequently found in ovarian cancer that initially resistant to PARP inhibition. By using this model, we will screen for new treatment targets and develop new treatment options for patients with Cyclin E1-overexpressing tumors.
The research proposed in this project rests on solid experience in mouse models of ovarian cancer and pharmacology and builds upon the breakthrough discovery that immune cells in the tumor surroundings mediate the resistance to PARP inhibitor treatment in ovarian cancer. The proposed study aims to elucidate new mechanisms of PARP inhibitor resistance and find new ways to treat ovarian cancer with initial or acquired resistance to PARP inhibitor treatment. This study will not only address fundamental scientific questions regarding formation of PARP inhibitor resistance in ovarian cancer treatment, will also provide novel treatment strategies against this disease.