# Prevention of paclitaxel-induced peripheral neuropathy with nilotinib

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2021 · $584,565

## Abstract

Abstract
Tubulin poisons such as paclitaxel (Taxol) are among the most widely used anticancer agents for the treatment
of multiple solid tumors, including metastatic breast cancer. However, the clinical use of paclitaxel is
associated with dose-limiting damage to peripheral nerves (peripheral neuropathy), which occurs in up to 80%
of patients, and this complication may limit further treatment or severe diminish quality of life. There is currently
no known specific treatment for paclitaxel-induced peripheral neuropathy, and mechanistic details of this side
effect remain poorly understood. We have recently found that the ability of paclitaxel to cause damage to
peripheral nerves is dependent on the organic anion transporting polypeptide (OATP), OATP1B2. In humans,
this process was found to be regulated by the closely related transporter, OATP1B1 that regulates cellular
uptake of paclitaxel into dorsal root ganglia, the main site of drug accumulation within the nervous system. We
found that the function of these transporters can be potently inhibited by the tyrosine kinase inhibitor (TKI)
nilotinib at physiologically achievable concentrations, and that pretreatment with nilotinib can prevent acute and
chronic paclitaxel-induced peripheral neuropathy in mice. In the current proposal, we outline two sets of related
studies that will further test and refine the validity of our central hypothesis that targeted inhibition of OAT1B1
function with nilotinib will specifically affect accumulation of paclitaxel in peripheral nerves and affect its
downstream toxic effects, without influencing the plasma pharmacokinetics of paclitaxel and without negatively
affecting antitumor properties: (i) The hypothesis that OATP1B1 can be modulated by nilotinib will be tested in
a Bayesian Phase 1b trial with adaptive dose selection using efficacy-toxicity trade-offs in patients with early-
stage breast cancer eligible to receive treatment with weekly paclitaxel. The recommended Phase 2 dose will
be defined as the lowest intermittent dose of nilotinib producing statistically significant inhibition of OATP1B1
from baseline as determined by validated surrogate endogenous probes in plasma; (ii) The hypothesis that
nilotinib can ameliorate the OATP1B1-dependent toxicities of paclitaxel will be tested prospectively using a
double-blind, placebo-controlled, randomized Phase 2 clinical trial involving patients with early-stage breast
cancer. The demonstration of reduced chemotherapy-induced toxicity through inhibition of a critical transporter
regulating access of paclitaxel to peripheral nerves will provide the foundation for studies in the future aimed at
ameliorating these agents' debilitating neurological side effect in routine clinical practice.

## Key facts

- **NIH application ID:** 10129321
- **Project number:** 5R01CA238946-03
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Shuiying Hu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $584,565
- **Award type:** 5
- **Project period:** 2019-04-17 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129321

## Citation

> US National Institutes of Health, RePORTER application 10129321, Prevention of paclitaxel-induced peripheral neuropathy with nilotinib (5R01CA238946-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10129321. Licensed CC0.

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