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.
Cisplatin is a drug commonly used in chemotherapy to treat cancers of the head and neck, lung, and cervix. Treatment with cisplatin results in toxicity to the kidneys in at least one-third of patients. We plan to study how genetic background and the body's handling of cisplatin contribute to kidney toxicity.
|Wen, Xia; Gibson, Christopher J; Yang, Ill et al. (2014) MDR1 transporter protects against paraquat-induced toxicity in human and mouse proximal tubule cells. Toxicol Sci 141:475-83|
|Wen, Xia; Buckley, Brian; McCandlish, Elizabeth et al. (2014) Transgenic expression of the human MRP2 transporter reduces cisplatin accumulation and nephrotoxicity in Mrp2-null mice. Am J Pathol 184:1299-308|