Cisplatin is one of the most widely used anticancer agents for the treatment of multiple malignant solid tumors in both adults and children. The clinical use of cisplatin is associated with dose-limiting kidney damage (nephrotoxicity), which is dependent on p53 and occurs in one-third of patients despite intensive prophylactic measures, and this complication may limit further treatment or even threaten life. There is currently no known specific treatment for cisplatin-induced renal dysfunction, and mechanistic details of renal handling of cisplatin have remained poorly studied. We have recently found that the urinary excretion of cisplatin and drug-induced damage to kidneys is dependent on organic cation transporter-mediated renal tubular transport. In mice, this process was found to be regulated by the two closely related organic cation transporters, Oct1 and Oct2, that are functionally redundant and that together fulfill a role equivalent to that of a single organic cation transporter, OCT2, in humans. These transporters are highly expressed on the basolateral membrane of renal tubular cells but we found that OCT2 is essentially absent in human cancer cell lines and human solid tumors, in particular in those for which treatment with cisplatin is indicated, such as lung cancer and ovarian cancer. These findings suggest that OCT2 is unlikely to play a role in the transport of cisplatin into tumor cells in vivo. In the current proposal, we outline three sets of related studies that will further test and refine the validity of our central hypothesis that targeted inhibition of OCT2 function will specifically affect cisplatin accumulation in proximal tubular cells and its downstream toxic effects. (1) Using various mouse models and a cohort of adult cancer patients, we will further determine the quantitative effects of OCT2 inhibitors on the disposition and toxicity of cisplatin. (2) Similar studies will be performed to determine the additional contribution of the p53 signaling pathway to cisplatin nephrotoxicity in mice concurrently receiving a dual OCT2/p53 inhibitor. (3) Additional studies in nu/nu mice bearing human tumor xenografts with variable expression levels of OCT2 will determine the direct contribution of this transporter to cisplatin-related anticancer efficacy. The demonstration of reduced cisplatin-induced nephrotoxicity through inhibition of a critical renal transporter regulating access of the drug to renal proximal tubular cells will provide the foundation for additional studies in the future aimed at ameliorating this debilitating side effect in routine clinical practice.

Public Health Relevance

Cisplatin is among the most effective and widely prescribed anticancer agents but its clinical use is associated with dose-limiting, irreversible kidney damage (nephrotoxicity). Using a unique genetic mouse model, we found that cisplatin nephrotoxicity is dependent on transporter-mediated drug uptake into renal tubular cells. Our proposed studies are of direct human relevance because targeted interference with the identified renal transport system may mitigate the incidence and severity of this debilitating side effect in humans.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA151633-05
Application #
8657878
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Timmer, William C
Project Start
2010-07-12
Project End
2015-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
City
Memphis
State
TN
Country
United States
Zip Code
38105
Sprowl, Jason A; Ong, Su Sien; Gibson, Alice A et al. (2016) A phosphotyrosine switch regulates organic cation transporters. Nat Commun 7:10880
Drenberg, C D; Paugh, S W; Pounds, S B et al. (2016) Inherited variation in OATP1B1 is associated with treatment outcome in acute myeloid leukemia. Clin Pharmacol Ther 99:651-60
Lanvers-Kaminsky, Claudia; Sprowl, Jason A; Malath, Ingrid et al. (2015) Human OCT2 variant c.808G>T confers protection effect against cisplatin-induced ototoxicity. Pharmacogenomics 16:323-32
Pabla, Navjotsingh; Gibson, Alice A; Buege, Mike et al. (2015) Mitigation of acute kidney injury by cell-cycle inhibitors that suppress both CDK4/6 and OCT2 functions. Proc Natl Acad Sci U S A 112:5231-6
Pabla, Navjotsingh; Sparreboom, Alex (2015) CCR 20th anniversary commentary: BMS-247550—microtubule stabilization as successful targeted therapy. Clin Cancer Res 21:1237-9
Mathijssen, Ron H J; Sparreboom, Alex; Verweij, Jaap (2014) Determining the optimal dose in the development of anticancer agents. Nat Rev Clin Oncol 11:272-81
Sprowl, Jason A; Lancaster, Cynthia S; Pabla, Navjotsingh et al. (2014) Cisplatin-induced renal injury is independently mediated by OCT2 and p53. Clin Cancer Res 20:4026-35
Sparreboom, Alex; Mathijssen, Ron H J (2014) Hepatic uptake transporters and docetaxel disposition in mice-letter. Clin Cancer Res 20:4167
Sprowl, Jason A; Sparreboom, Alex (2014) Uptake carriers and oncology drug safety. Drug Metab Dispos 42:611-22
de Graan, Anne-Joy M; Elens, Laure; Sprowl, Jason A et al. (2013) CYP3A4*22 genotype and systemic exposure affect paclitaxel-induced neurotoxicity. Clin Cancer Res 19:3316-24

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