Ovarian cancer is the fifth leading cause of cancer deaths among women in the United States. Currently, the five-year survival rate from ovarian cancer is only 20% to 30%. The treatment of ovarian cancer is limited by drug resistance, which is primarily mediated by proteins known as ABC transporters. These proteins act to transport or pump numerous drugs from the inside of the cancer cell to the outside. This is important as this process will decrease the effectiveness of the drug against the cancer cells. The current standard of treatment for ovarian cancer usually is the drugs paclitaxel and cisplatin. However, most patients with advanced stages of the disease fail to respond to treatment after an initial response. Paclitaxel is frequently used for the treatment of several types of tumors such as ovarian cancer, breast cancer and non-small-cell lung cancer. The clinical response rate to paclitaxel is often limited by the rapid development of resistance to the drug in women with recurrent ovarian cancer. P-glycoprotein, an ABC transporter, is one of the major factors that produce resistance to paclitaxel. However, resistance to paclitaxel is also observed in clinical samples that do not express P- gp. This suggests that other processes are present that can produce drug resistance in the cancer cells. Therefore, the discovery of other mechanisms of drug resistance to paclitaxel in ovarian cancer is important for the development of treatments that may attenuate or prevent paclitaxel resistance in ovarian cancer patients. Recent reports showed that another ABC transporter, MRP7, can also produce cellular resistance to paclitaxel. Currently, it is unknown as to whether MRP7 plays a role in mediating resistance to ovarian cancer treatment. If MRP7 is discovered to contribute significantly to drug resistance, it is possible that the inhibition of MRP7 may offer an approach for treating ovarian cancer cells resistant to treatment. The purpose of the study is to determine if MRP7 plays a role in mediating paclitaxel resistance in ovarian cancer. First, a mouse model was used to determine if MRP7 produces resistance to paclitaxel. In addition, it will be determined if the level of expression of MRP7 and P-gp can be used to predict resistance to treatment in addition to be a prognostic factor in ovarian cancer treatment. Finally, novel inhibitors of MRP7 will be identified, which may ultimately improve the therapeutic response by increasing the concentration of drug that remains inside of the cancer cells. The results of these studies should provide valuable information about 1) the involvement of MRP7 and P-gp in producing ovarian cancer cell resistance to paclitaxel and 2) whether certain chemical substances can inhibit the MRP7 pump in drug resistant cancer cells. The new discovered compounds that when combined with paclitaxel may improve clinical response and survival in patients with recurrent ovarian cancer by overcoming the resistance to paclitaxel.
The research proposed in this grant application will increase our knowledge about the mechanisms of paclitaxel-mediated resistance in ovarian cancer. In addition, it can potentially lead to the discovery of new compounds that may be effective in reducing or reversing the decreased response to paclitaxel, drugs that are part of the treatment regimen for ovarian cancer. Finally, the knowledge obtained from this research could assist physicians in improving survival rate of ovarian cancer patients.
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