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

描述(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，耐药性主要由ABC转运蛋白介导。这些蛋白质的作用是将许多药物从癌细胞内部输送到外部。这一点很重要，因为这一过程将降低药物对癌细胞的有效性。目前卵巢癌的治疗标准通常是紫杉醇和顺铂。然而，大多数晚期患者在最初的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。复发性卵巢癌患者对紫杉醇的临床应答率往往受到药物耐药性快速发展的限制。P-糖蛋白是一种ABC转运蛋白，是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。这表明存在其他能在癌细胞中产生抗药性的过程。因此，发现卵巢癌对紫杉醇耐药的其他机制对于开发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。最近的报道显示，另一种ABC转运蛋白MRP7也能产生细胞对紫杉醇的耐药性。目前，MRP7是否在卵巢癌治疗耐药中起中介作用尚不清楚。如果MRP7被发现与耐药性有关，那么抑制MRP7有可能为治疗耐药的卵巢癌细胞提供一种新的途径。该研究的目的是确定MRP7是否在卵巢癌的紫杉醇耐药中发挥作用。首先，使用小鼠模型来确定MRP7是否对紫杉醇产生耐药性。此外，还将确定MRP7和P-gp的表达水平除了可作为卵巢癌治疗的预后因素外，是否还可用于预测耐药。最后，将确定新的MRP7抑制剂，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。这些研究的结果将为以下方面提供有价值的信息：1)MRP7和P-gp参与了卵巢癌细胞对紫杉醇的耐药性；2)某些化学物质是否能抑制耐药癌细胞中的MRP7泵。新发现的化合物，当与紫杉醇联合使用时，可能通过克服紫杉醇的耐药性来改善复发卵巢癌患者的临床反应和生存率。 公共卫生相关性：这项拨款申请中提出的研究将增加我们对紫杉醇介导的卵巢癌耐药机制的了解。此外，它可能会导致发现新的化合物，这些化合物可能有效地减少或逆转对紫杉醇的反应减弱，紫杉醇是卵巢癌治疗方案的一部分。最后，从本研究中获得的知识可以帮助医生提高卵巢癌患者的生存率。

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.