Our laboratory focuses on the early detection and prevention of ovarian cancer, studies of cell growth regulation (ovarian and breast carcinomas); research into imprinted tumor suppressor genes; the manipulation of cancer autophagy and tumor dormancy; and research into the modulation of taxane, platinum and PARP (the enzyme poly ADP ribose polymerase) inhibitor sensitivity.
1. Function of imprinted tumor suppressor genes that are downregulated in ovarian cancer. Our lab has characterized an imprinted tumor suppressor gene DIRAS3 (ARHI) that encodes a 26kD GTPase with 50% homology to Ras. DIRAS3 is downregulated in 60% of ovarian cancers associated with decreased disease free survival. Downregulation of DIRAS3 has been observed in cancers that arise at many sites including breast, lung, prostate, pancreas, thyroid and brain. Re-expression of DIRAS inhibits proliferation and motility, while inducing autophagy and tumor dormancy. DIRAS3 has been shown to inhibit Ras induced transformation and to disrupt Ras clustering. DIRAS3 also inhibits both PI3K and MAPK signaling and participates directly in autophagosome formation. In cell culture, expression of DIRAS3 leads to cell death, but in xenografts DIRAS expression and autophagy are associated with tumor dormancy. Our group has developed the first inducible model for tumor dormancy in ovarian cancer, permitting evaluation of novel therapy to eliminate dormant ovarian cancer cells. Currently our studies are focus on trying to determine the mechanisms underlying DIRAS3-induced autophagy and requirements for survival of dormant ovarian cancer cells.
2. Individualized enhancement of primary sensitivity to paclitaxel in different ovarian cancers. Most ovarian cancer patients receive a combination of carboplatin and paclitaxel chemotherapy, but less than half respond to paclitaxel. Enhanced response to primary chemotherapy could improve outcomes in the majority of non-responders by combining targeted therapy with paclitaxel. Through high throughput Kinome siRNA screen we identified more than 30 kinases that regulate paclitaxel sensitivity in ovarian cancer cells. Knockdown of kinases such as IKBKB and STK39 enhance paclitaxel sensitivity by increasing microtubule stability regulated by microtubule associated protein 4 (MAP4). Knockdown of kinases that modulate the pentose phosphate shunt such as PFKFB2 also enhance the response to paclitaxel in ovarian and breast cancer cells with wild type TP53. Knockdown of Salt-inducible Kinase 2 (SIK2) enhanced sensitivity to paclitaxel, inducing polyploidy and inhibiting PI3K activity. SIK2 encodes an AMP-like kinase that is overexpressed in 30% of ovarian cancers, associated with decreased survival. We discovered that SIK2 localizes to the centrosome and is required for centrosome splitting. It also regulates PI3 kinase activity and class IIa HDAC phosphorylation and nuclear localization. SIK2 has been targeted with siRNA in nanoparticles and with the low molecular weight inhibitors ARN-2236 and ARN-3261. The latter is expected to enter phase I clinical trials this year.
3. Identification of biomarkers and strategies for early detection of ovarian cancer. Having Having developed the first monoclonal antibodies that react with epithelial ovarian cancer, including OC125, my group had discovered the CA125 antigen, leading to the development of the first clinically useful biomarker for monitoring ovarian cancer. In recent years, we have identified a panel of four serum biomarkers, including CA125, which detects more than 80% of early-stage ovarian cancer. Anti-TP53 autoantibodies have been shown to detect 20% of cases missed by CA125 and to increase 8 months prior to CA125 or 22 months prior to diagnosis when CA125 is not elevated. An algorithm is being developed to include CA125, HE4, CA72.4 and autoantibodies against TP53.