Targeting MRP7 to Overcome Drug Resistance for Ovarian Cancer Therapy by Taxanes

描述（由申请人提供）：卵巢癌是美国女性癌症死亡的第五大原因。目前，卵巢癌的五年生存率只有20%到30%。卵巢癌的治疗受到耐药性的限制，耐药性主要是由ABC转运蛋白介导的。这些蛋白质的作用是将大量药物从癌细胞内部输送到外部。这很重要，因为这个过程会降低药物对癌细胞的有效性。目前治疗卵巢癌的标准药物通常是紫杉醇和顺铂。然而，大多数晚期患者在最初有反应后对治疗没有反应。紫杉醇经常用于治疗几种类型的肿瘤，如卵巢癌、乳腺癌和非小细胞肺癌。临床对紫杉醇的反应率往往受到卵巢癌复发妇女对该药快速耐药的限制。糖蛋白是一种ABC转运蛋白，是产生紫杉醇耐药的主要因素之一。然而，在不表达P- gp的临床样本中也观察到对紫杉醇的耐药性。这表明在癌细胞中存在其他可以产生耐药性的过程。因此，发现卵巢癌中紫杉醇耐药的其他机制对于开发可能减轻或预防卵巢癌患者紫杉醇耐药的治疗方法具有重要意义。最近的报道表明，另一种ABC转运蛋白MRP7也可以产生紫杉醇的细胞抗性。目前尚不清楚MRP7是否在介导卵巢癌治疗耐药中发挥作用。如果MRP7被发现对耐药有显著贡献，那么抑制MRP7可能为治疗耐药卵巢癌细胞提供一种方法。本研究的目的是确定MRP7是否在介导卵巢癌紫杉醇耐药中发挥作用。首先，使用小鼠模型来确定MRP7是否产生对紫杉醇的抗性。此外，MRP7和P-gp的表达水平是否可作为卵巢癌治疗的预后因素，并可用于预测治疗耐药。最后，新的MRP7抑制剂将被鉴定出来，这可能最终通过增加留在癌细胞内的药物浓度来改善治疗反应。这些研究结果将为以下方面提供有价值的信息：1)MRP7和P-gp是否参与卵巢癌细胞对紫杉醇的耐药性产生；2)某些化学物质是否可以抑制耐药癌细胞中的MRP7泵。新发现的化合物与紫杉醇联合可通过克服对紫杉醇的耐药来改善复发性卵巢癌患者的临床反应和生存。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.