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

靶向 MRP7 克服紫杉烷类药物治疗卵巢癌的耐药性

• 批准号: 7778743
• 负责人: Zhe-Sheng Chen
• 金额: $ 24.53万
• 依托单位: ST. JOHN'S UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-08 至 2013-02-07
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7778743
• 关键词: ABCB1 gene; ABCG2 gene; ATP-Binding Cassette Transporters; Aftercare; Applications Grants; Attenuated; Binding; Biological Assay; Biological Models; Bromides; Cancer Etiology; Cancer Patient; Cancer cell line; Cell Line; Cessation of life; Chemicals; Cisplatin; Clinical; Collaborations; Development; Disease; Drug Efflux; Drug resistance; Effectiveness; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Erlotinib; Fluorescence; Foxes; Gynecologic; Human; Immunoblot Analysis; Immunohistochemistry; Implant; Individual; Knockout Mice; Knowledge; Lead; Louisiana; Malignant Neoplasms; Malignant neoplasm of ovary; Marines; Mediating; Membrane; Multi-Drug Resistance; Mus; Non-Small-Cell Lung Carcinoma; Nude Mice; P-Glycoprotein; P-Glycoproteins; Paclitaxel; Patients; Pharmaceutical Preparations; Pharmacy Schools; Physicians; Play; Porifera; Process; Prognostic Factor; Proteins; Pump; Recurrence; Recurrent disease; Red Sea; Reporting; Research; Resistance; Role; Sampling; Solid Neoplasm; Source; Specimen; Staging; Survival Rate; Taxane Compound; Therapeutic; Time; Transgenic Mice; Transgenic Model; Transport Vesicles; Treatment Protocols; Tyrosine Kinase Inhibitor; United States; Universities; Woman; Xenograft Model; Xenograft procedure; base; cancer cell; cancer therapy; cell growth; docetaxel; drug mechanism; expression vector; improved; in vitro Assay; in vivo; inhibitor/antagonist; insight; lapatinib; malignant breast neoplasm; mouse model; novel; ovarian neoplasm; prevent; prognostic; programs; public health relevance; resistance factors; resistance mechanism; response; standard care; taxane; therapy development; tumor; uptake

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.

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仅为20%至30%。卵巢癌的治疗受到耐药性的限制，耐药性主要由称为ABC转运蛋白的蛋白质介导。这些蛋白质的作用是将许多药物从癌细胞内部运输或泵送到癌细胞外部。这一点很重要，因为这个过程会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。对紫杉醇的临床反应率通常受到复发性卵巢癌妇女对药物迅速产生耐药性的限制。P-糖蛋白是一种ABC转运蛋白，是导致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。这表明存在其他可以在癌细胞中产生耐药性的过程。因此，发现卵巢癌对紫杉醇耐药的其他机制对于开发可能减弱或预防卵巢癌患者对紫杉醇耐药的治疗非常重要。最近的报告显示，另一种ABC转运蛋白MRP 7也可以产生对紫杉醇的细胞耐药性。目前，还不清楚MRP 7是否在介导卵巢癌治疗耐药性中发挥作用。如果发现MRP 7对耐药性有重要作用，那么抑制MRP 7可能为治疗卵巢癌细胞耐药提供一种方法。该研究的目的是确定MRP 7是否在卵巢癌中介导紫杉醇耐药中发挥作用。首先，使用小鼠模型来确定MRP 7是否产生对紫杉醇的抗性。此外，还将确定MRP 7和P-gp的表达水平除了作为卵巢癌治疗的预后因素外，是否还可用于预测对治疗的抵抗。最后，将确定新型MRP 7抑制剂，这可能最终通过增加保留在癌细胞内的药物浓度来改善治疗反应。这些研究的结果应该提供关于1）MRP 7和P-gp参与产生卵巢癌细胞对紫杉醇的耐药性和2）某些化学物质是否可以抑制耐药癌细胞中的MRP 7泵的有价值的信息。新发现的化合物，当与紫杉醇结合时，可以通过克服对紫杉醇的耐药性来改善复发性卵巢癌患者的临床反应和生存率。 公共卫生关系：这项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降低，紫杉醇是卵巢癌治疗方案的一部分。最后，本研究所获得的知识可以帮助医生提高卵巢癌患者的生存率。

项目成果

OSI-930 analogues as novel reversal agents for ABCG2-mediated multidrug resistance.

• DOI: 10.1016/j.bcp.2012.06.019
• 发表时间: 2012-09-15
• 期刊: BIOCHEMICAL PHARMACOLOGY
• 影响因子: 5.8
• 作者: Kuang, Ye-Hong;Patel, Jay P.;Sodani, Kamlesh;Wu, Chung-Pu;Liao, Li-Qiu;Patel, Atish;Tiwari, Amit K.;Dai, Chun-Ling;Chen, Xiang;Fu, Li-Wu;Ambudkar, Suresh V.;Korlipara, Vijaya L.;Chen, Zhe-Sheng
• 通讯作者: Chen, Zhe-Sheng

Modulating the function of ATP-binding cassette subfamily G member 2 (ABCG2) with inhibitor cabozantinib.

• DOI: 10.1016/j.phrs.2017.01.024
• 发表时间: 2017-05
• 期刊: Pharmacological research
• 影响因子: 9.3
• 作者: Zhang GN;Zhang YK;Wang YJ;Barbuti AM;Zhu XJ;Yu XY;Wen AW;Wurpel JND;Chen ZS
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Tandutinib (MLN518) reverses multidrug resistance by inhibiting the efflux activity of the multidrug resistance protein 7 (ABCC10).

• DOI: 10.3892/or.2013.2362
• 发表时间: 2013-06
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• 影响因子: 4.2
• 作者: Deng W;Dai CL;Chen JJ;Kathawala RJ;Sun YL;Chen HF;Fu LW;Chen ZS
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Roles of sildenafil in enhancing drug sensitivity in cancer.

• DOI: 10.1158/0008-5472.can-11-0375
• 发表时间: 2011-06-01
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Shi Z;Tiwari AK;Patel AS;Fu LW;Chen ZS
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Reversal of MRP7 (ABCC10)-mediated multidrug resistance by tariquidar.

• DOI: 10.1371/journal.pone.0055576
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Sun YL;Chen JJ;Kumar P;Chen K;Sodani K;Patel A;Chen YL;Chen SD;Jiang WQ;Chen ZS
• 通讯作者: Chen ZS