# (9) Therapeutic strategies to mitigate toxicities of platinum-based therapeutics

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2021 · $512,366

## Abstract

ABSTRACT
Cisplatin is one of the most widely used anticancer agents, including for the treatment of solid tumors in
children and adults. The clinical use of cisplatin is associated with dose-limiting damage to renal tubular cells
(nephrotoxicity), which occurs in up to 40% of patients despite intensive prophylactic measures, as well as with
toxicity to cochlea (ototoxicity) and peripheral nerves (neurotoxicity), and these complications may limit further
treatment or even threaten life. There is currently no known specific treatment for cisplatin-induced toxicities,
and mechanistic details of these side effects remain poorly understood. We have recently found that the ability
of platinum chemotherapeutics to cause damage to healthy tissues cells is dependent on organic cation
transporters (OCT) and, for renal tubular cells, organic anion transporters (OAT) as well. In mice, these
processes were found to be regulated by the two pairs of closely related transporters, Oct1/Oct2 that regulate
cellular uptake of cisplatin, and Oat1/Oat3 that regulate renal uptake of a cisplatin mercapturic acid metabolite
that acts as a precursor of a potent nephrotoxin. We found that the function of these 4 transporters can be
potently inhibited by the tyrosine kinase inhibitor nilotinib, through non-competitive mechanisms. 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 OCT and OAT function with nilotinib will specifically affect accumulation of
cisplatin in healthy target tissues and affect its downstream toxic effects: (i) Using various in vitro and in vivo
models, including zebrafish and mice, we will further determine the qualitative and quantitative effects of
nilotinib on the function of Oct1/Oct2 and Oat1/Oat3; (ii) Studies in zebrafish and mice with or without specific
transporters and kinases of interest will determine the direct contribution of these proteins to cisplatin-related
toxicity, including nephrotoxicity, ototoxicity, and neurotoxicity, as well as drug disposition properties and drug-
drug interaction potentials; (iii) Using mice with or without human tumor xenografts derived from replicating cell
lines or patient tumors, we will determine the direct contribution of these proteins to cisplatin-related anticancer
efficacy, and the in vivo effects of nilotinib on this phenotype. The demonstration of reduced cisplatin-induced
toxicity through inhibition of critical transporters regulating access of the drug to healthy tissues will provide the
foundation for additional studies in the future aimed at ameliorating this agent's debilitating side effects in
routine clinical practice.

## Key facts

- **NIH application ID:** 10133537
- **Project number:** 5R01CA215802-05
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Navjot Pabla
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $512,366
- **Award type:** 5
- **Project period:** 2017-04-03 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133537

## Citation

> US National Institutes of Health, RePORTER application 10133537, (9) Therapeutic strategies to mitigate toxicities of platinum-based therapeutics (5R01CA215802-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10133537. Licensed CC0.

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