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.
Tubulin poisons such as paclitaxel (Taxol) are among the most effective and widely prescribed anticancer agents but their clinical use is associated with dose-limiting damage to peripheral nerves (neuropathy). Using a unique genetic mouse model, we found that acute and chronic peripheral neuropathy of paclitaxel is dependent on transporter-mediated drug uptake. The proposed studies are a logical continuation of our prior studies and will directly test the hypothesis that targeted interference of the identified transport system with the tyrosine kinase inhibitor nilotinib can mitigate the incidence and severity of these debilitating side effects in humans.
