Pharmacokinetic and Pharmacogenomic Determinants of Cisplatin Kidney Injury

描述(申请人提供)：顺铂是一种含金属的无机化疗药物，可有效治疗多种实体癌症。不幸的是，三分之一服用顺铂的患者会发生急性肾损伤，这可能导致治疗中断或剂量减少，从而影响肿瘤消退、患者生存和慢性肾损害的可能性。目前迫切需要探索导致癌症患者顺铂肾毒性的新机制。这项赠款申请侧重于肾毒性的决定因素，包括药物代谢、转运和直接影响肾小管暴露于顺铂的调节途径。在这项赠款申请中，我们建议进行一项转译研究，以调查控制顺铂肾损伤的药代动力学和药物基因组决定因素。具体地说，我们打算证明肾脏转运蛋白(OCT2/SLC22A2、MATE1/SLC47A1和MRP2/ABCC2)、谷胱甘肽代谢酶(谷胱甘肽-S转移酶，例如GSTP1和GSTA1，以及g-谷氨酰转移酶1，例如GGT1)和转录因子NRF2/NFE2L2是顺铂暴露和肾毒性的重要决定因素。由于调控这些蛋白质的基因主要在肾脏中表达，因此这项赠款申请侧重于影响肾脏顺铂暴露的因素。建议的研究结合了临床肾毒性的传统方法(血肌酐、血尿素氮)和一种新的生物标记物(尿金-1)来检测急性肾损伤的表型。我们研究的中心假设是，药物动力学参数和顺铂相关代谢和转运途径中的遗传变异是预测服用顺铂化疗的癌症患者肾毒性的生物标志物。为了验证这些假设，我们将1)测量顺铂在血浆和尿液中的游离浓度和总浓度，以及2)评估与顺铂代谢和转运相关的7个基因(SLC22A2、SLC47A1、ABCC2、NFE2L2、GSTA1、GSTP1、GGT1)的遗传变异。这七个基因之前已经被证明在细胞和动物系统中影响肾毒性。这些结果的预期影响包括通过修改顺铂的给药减少肾脏暴露的重大转化机会，在化疗开始之前识别“危险”患者，以及确保患者接受整个疗程，以便他们能够获得最大的根治机会。这项研究的长期好处是减少了接受顺铂治疗的癌症患者的急性和慢性肾毒性的发生率，并提高了化疗治愈率。拟议的研究将产生比目前研究更高的影响，因为它整合了预防顺铂肾毒性的个性化药物方法，作为未来研究其他药物引起的肾毒性的基础，并为生物标记物提供更多的应用。

DESCRIPTION (provided by applicant): Cisplatin is an inorganic metal-containing chemotherapeutic agent used to effectively treat a myriad of solid cancers. Unfortunately, acute kidney injury occurs in one-third of patients prescribed cisplatin and this can result in therapy discontinuation or dosage reductions that impact tumor regression, patient survival, and likelihood of chronic kidney damage. There is an urgent need to explore novel mechanisms that contribute to cisplatin nephrotoxicity in cancer patients. This grant application focuses on determinants of nephrotoxicity including drug metabolism, transport, and regulatory pathways that directly influence the exposure of kidney tubules to cisplatin. In this grant application, we propose a translational study to investigate pharmacokinetic and pharmacogenomic determinants that govern kidney injury to cisplatin. Specifically, we intend to demonstrate that genetic variants in kidney transporters (OCT2/SLC22A2, MATE1/SLC47A1, and MRP2/ABCC2), glutathione metabolizing enzymes (Glutathione-S-transferases, e.g. GSTP1 and GSTA1, and g-glutamyl transferase1, e.g. GGT1), and the NRF2/NFE2L2 transcription factor are important determinants of cisplatin exposure and nephrotoxicity. Since the genes regulating these proteins are predominantly expressed in kidney, this grant application focuses on factors affecting renal exposure to cisplatin. The proposed studies incorporate traditional measures of clinical nephrotoxicity (serum creatinine, blood urea nitrogen) and a novel biomarker (urinary Kim-1) to detect the phenotype of acute kidney injury. The Central Hypotheses of our research are that pharmacokinetic parameters and genetic variants in cisplatin-relevant metabolic and transport pathways are biomarkers predictive of nephrotoxicity in cancer patients who are prescribed cisplatin-containing chemotherapy. In order to test these hypotheses, we will 1) measure free and total cisplatin concentrations in plasma and urine, and 2) evaluate genetic variants in seven genes (SLC22A2, SLC47A1, ABCC2, NFE2L2, GSTA1, GSTP1, GGT1) relevant to the metabolism and transport of cisplatin. These seven genes have been previously shown to influence nephrotoxicity in cell- and animal-based systems. The anticipated impact of these results include significant translational opportunities to reduce exposure of the kidney by modifying administration of cisplatin, to identify "at risk" patients prir to chemotherapy initiation, and to insure patients receive an entire course of therapy so they can have the greatest chance of curative therapy. The long-term benefits of this research are a reduced incidence of acute and chronic nephrotoxicity in cancer patients receiving cisplatin and enhanced chemotherapy cure rates. The proposed research would have high impact beyond the current study by integrating a personalized medicine approach to prevent cisplatin nephrotoxicity, serving as a basis for future study of other drug-induced nephrotoxicities, and provision of additional applications for biomarkers.