Ovarian high-grade serous carcinoma (HGSC) is a common and aggressive type of ovarian cancer. It accounts for 70% of overall ovarian cancer deaths and is a key contributor to the low five-year survival rate and overall mortality of ovarian cancer. The reason for the dismal outcome associated with ovarian HGSC is largely due to high occurrence of recurrent diseases after conventional first line therapy. Despite responding well initially, the majority of the patients will relapse as a result of chemoresistance within approximately 18 months. When the disease recurred, it is generally incurable with >90% mortality rate. Thus, there is an unmet need to develop effective therapy for recurrent chemoresistant ovarian HGSC.
To discover potential therapeutic targets for recurrent ovarian HGSC, our laboratory has compared the proteomes between primary untreated and recurrent post-carboplatin/paclitaxel treated HGSC tissues using mass spectrometry. From this screen, we identified Spleen Tyrosine Kinase (SYK) which is significantly more abundant in the recurrent tumors than the primary tumors in the same patients. However, little studies have actually examined the role of SYK in ovarian cancers until recently. We validated that SYK was not only overexpressed, but also activated in these recurrent tumors by examining its phosphorylation in another cohort of patients. More importantly, inhibition of SYK activity using small molecule inhibitors can significantly enhance anti-tumor efficacy of paclitaxel in cell culture systems, as well as human ovarian cancer grown in immunodeficient mice. Based on these findings, we propose that SYK may be involved in mediating the progression of drug resistance in recurrent ovarian cancers, and is a promising target.
In this project, we will investigate the molecular mechanisms of how SYK contributes to chemoresistance and conduct a comprehensive pre-clinical study using a chemoresistant mouse model to test the efficacy of orally active SYK inhibitor. The results from this proposal are expected to lay a basic translational groundwork for introducing a new regimen to sensitize chemotherapy in order to overcome drug resistance in ovarian cancer patients.