Program Official

Principal Investigator

Shuiying
Hu
Awardee Organization

Ohio State University
United States

Fiscal Year
2023
Activity Code
R01
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Prevention of paclitaxel-induced peripheral neuropathy with nilotinib

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 earlystage 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.

Publications

  • Huang KM, Hu S. Targeting drug transporters to prevent chemotherapy-induced peripheral neuropathy. Molecular & cellular oncology. 2020 Dec 1;8(1):1838863. doi: 10.1080/23723556.2020.1838863. eCollection 2021. PMID: 33553600
  • Chan A, Hertz DL, Morales M, Adams EJ, Gordon S, Tan CJ, Staff NP, Kamath J, Oh J, Shinde S, Pon D, Dixit N, D'Olimpio J, Dumitrescu C, Gobbo M, Kober K, Mayo S, Pang L, Subbiah I, Beutler AS, Peters KB, Loprinzi C, Lustberg MB. Biological predictors of chemotherapy-induced peripheral neuropathy (CIPN): MASCC neurological complications working group overview. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2019 Oct;27(10):3729-3737. Epub 2019 Jul 30. PMID: 31363906
  • Uddin ME, Moseley A, Hu S, Sparreboom A. Contribution of membrane transporters to chemotherapy-induced cardiotoxicity. Basic & clinical pharmacology & toxicology. 2022 Jan;130 Suppl 1:36-47. Epub 2021 Jul 21. PMID: 34237188
  • Anderson JT, Hu S, Fu Q, Baker SD, Sparreboom A. Role of equilibrative nucleoside transporter 1 (ENT1) in the disposition of cytarabine in mice. Pharmacology research & perspectives. 2019 Dec 2;7(6):e00534. doi: 10.1002/prp2.534. eCollection 2019 Dec. PMID: 31832201
  • Jin Y, Li Y, Eisenmann ED, Figg WD, Baker SD, Sparreboom A, Hu S. Determination of the endogenous OATP1B biomarkers glycochenodeoxycholate-3-sulfate and chenodeoxycholate-24-glucuronide in human and mouse plasma by a validated UHPLC-MS/MS method. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences. 2022 Nov 1;1210:123437. Epub 2022 Aug 27. PMID: 36054985
  • Chen M, Hu S, Li Y, Gibson AA, Fu Q, Baker SD, Sparreboom A. Role of Oatp2b1 in Drug Absorption and Drug-Drug Interactions. Drug metabolism and disposition: the biological fate of chemicals. 2020 May;48(5):419-425. Epub 2020 Feb 29. PMID: 32114507
  • Li Y, Talebi Z, Chen X, Sparreboom A, Hu S. Endogenous Biomarkers for SLC Transporter-Mediated Drug-Drug Interaction Evaluation. Molecules (Basel, Switzerland). 2021 Sep 10;26. (18). PMID: 34576971
  • Dwivedi P, Han S, Mangrio F, Fan R, Dwivedi M, Zhu Z, Huang F, Wu Q, Khatik R, Cohn DE, Si T, Hu S, Sparreboom A, Xu RX. Corrigendum to "Engineered multifunctional biodegradable hybrid microparticles for paclitaxel delivery in cancer therapy" [Mater Sci Eng C 102 (2019) 113-123]. Materials science & engineering. C, Materials for biological applications. 2020 Mar;108:110326. Epub 2019 Nov 20. PMID: 31924044
  • Uddin ME, Garrison DA, Kim K, Jin Y, Eisenmann ED, Huang KM, Gibson AA, Hu Z, Sparreboom A, Hu S. Influence of YES1 Kinase and Tyrosine Phosphorylation on the Activity of OCT1. Frontiers in pharmacology. 2021 Mar 8;12:644342. doi: 10.3389/fphar.2021.644342. eCollection 2021. PMID: 33790797
  • Uddin ME, Sun X, Huang KM, Hu S, Carnes CA, Sparreboom A, Fu Q. Development and validation of a UPLC-MS/MS analytical method for dofetilide in mouse plasma and urine, and its application to pharmacokinetic study. Journal of pharmaceutical and biomedical analysis. 2019 Aug 5;172:183-188. Epub 2019 Apr 19. PMID: 31055183
  • Li Y, Jin Y, Taheri H, Schmidt KT, Gibson AA, Buck SAJ, Eisenmann ED, Mathijssen RHJ, Figg WD, Baker SD, Sparreboom A, Hu S. A Metabolomics Approach for Predicting OATP1B-Type Transporter-Mediated Drug-Drug Interaction Liabilities. Pharmaceutics. 2022 Sep 13;14. (9). PMID: 36145680
  • Huang KM, Uddin ME, DiGiacomo D, Lustberg MB, Hu S, Sparreboom A. Role of SLC transporters in toxicity induced by anticancer drugs. Expert opinion on drug metabolism & toxicology. 2020 Jun;16(6):493-506. Epub 2020 Apr 26. PMID: 32276560
  • Marie S, Hernández-Lozano I, Breuil L, Truillet C, Hu S, Sparreboom A, Tournier N, Langer O. Imaging-Based Characterization of a Slco2b1(-/-) Mouse Model Using [11C]Erlotinib and [99mTc]Mebrofenin as Probe Substrates. Pharmaceutics. 2021 Jun 21;13. (6). PMID: 34205780
  • Li Y, Drabison T, Nepal M, Ho RH, Leblanc AF, Gibson AA, Jin Y, Yang W, Huang KM, Uddin ME, Chen M, DiGiacomo DF, Chen X, Razzaq S, Tonniges JR, McTigue DM, Mims AS, Lustberg MB, Wang Y, Hummon AB, Evans WE, Baker SD, Cavaletti G, Sparreboom A, Hu S. Targeting a xenobiotic transporter to ameliorate vincristine-induced sensory neuropathy. JCI insight. 2023 Jul 24;8. (14). PMID: 37347545
  • Mezzanotte JN, Grimm M, Shinde NV, Nolan T, Worthen-Chaudhari L, Williams NO, Lustberg MB. Updates in the Treatment of Chemotherapy-Induced Peripheral Neuropathy. Current treatment options in oncology. 2022 Jan;23(1):29-42. Epub 2022 Feb 15. PMID: 35167004
  • Uddin ME, Eisenmann ED, Li Y, Huang KM, Garrison DA, Talebi Z, Gibson AA, Jin Y, Nepal M, Bonilla IM, Fu Q, Sun X, Millar A, Tarasov M, Jay CE, Cui X, Einolf HJ, Pelis RM, Smith SA, Radwański PB, Sweet DH, König J, Fromm MF, Carnes CA, Hu S, Sparreboom A. MATE1 Deficiency Exacerbates Dofetilide-Induced Proarrhythmia. International journal of molecular sciences. 2022 Aug 3;23. (15). PMID: 35955741
  • Brouwer KLR, Evers R, Hayden E, Hu S, Li CY, Meyer Zu Schwabedissen HE, Neuhoff S, Oswald S, Piquette-Miller M, Saran C, Sjöstedt N, Sprowl JA, Stahl SH, Yue W. Regulation of Drug Transport Proteins-From Mechanisms to Clinical Impact: A White Paper on Behalf of the International Transporter Consortium. Clinical pharmacology and therapeutics. 2022 Sep;112(3):461-484. Epub 2022 May 24. PMID: 35390174
  • Bonsu JM, Guha A, Charles L, Yildiz VO, Wei L, Baker B, Brammer JE, Awan F, Lustberg M, Reinbolt R, Miller ED, Jneid H, Ruz P, Carter RR, Milks MW, Paskett ED, Addison D. Reporting of Cardiovascular Events in Clinical Trials Supporting FDA Approval of Contemporary Cancer Therapies. Journal of the American College of Cardiology. 2020 Feb 18;75(6):620-628. PMID: 32057377
  • Lustberg M, Wu X, Fernández-Martínez JL, de Andrés-Galiana EJ, Philips S, Leibowitz J, Schneider B, Sonis S. Identification of a SNP cluster associated with taxane-induced peripheral neuropathy risk in patients being treated for breast cancer using GWAS data derived from a large cooperative group trial. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2023 Jan 28;31(2):139. PMID: 36707490
  • Huang KM, Zavorka Thomas M, Magdy T, Eisenmann ED, Uddin ME, DiGiacomo DF, Pan A, Keiser M, Otter M, Xia SH, Li Y, Jin Y, Fu Q, Gibson AA, Bonilla IM, Carnes CA, Corps KN, Coppola V, Smith SA, Addison D, Nies AT, Bundschuh R, Chen T, Lustberg MB, Wang J, Oswald S, Campbell MJ, Yan PS, Baker SD, Hu S, Burridge PW, Sparreboom A. Targeting OCT3 attenuates doxorubicin-induced cardiac injury. Proceedings of the National Academy of Sciences of the United States of America. 2021 Feb 2;118. (5). PMID: 33495337
  • Nepal MR, Taheri H, Li Y, Talebi Z, Uddin ME, Jin Y, DiGiacomo DF, Gibson AA, Lustberg MB, Hu S, Sparreboom A. Targeting OCT2 with Duloxetine to Prevent Oxaliplatin-Induced Peripheral Neurotoxicity. Cancer research communications. 2022 Nov;2(11):1334-1343. Epub 2022 Nov 3. PMID: 36506732
  • Hu S, Huang KM, Adams EJ, Loprinzi CL, Lustberg MB. Recent Developments of Novel Pharmacologic Therapeutics for Prevention of Chemotherapy-Induced Peripheral Neuropathy. Clinical cancer research : an official journal of the American Association for Cancer Research. 2019 Nov 1;25(21):6295-6301. Epub 2019 May 23. PMID: 31123053
  • Buelow DR, Anderson JT, Pounds SB, Shi L, Lamba JK, Hu S, Gibson AA, Goodwin EA, Sparreboom A, Baker SD. DNA Methylation-Based Epigenetic Repression of SLC22A4 Promotes Resistance to Cytarabine in Acute Myeloid Leukemia. Clinical and translational science. 2021 Jan;14(1):137-142. Epub 2020 Sep 9. PMID: 32905646
  • Li Y, Lustberg MB, Hu S. Emerging Pharmacological and Non-Pharmacological Therapeutics for Prevention and Treatment of Chemotherapy-Induced Peripheral Neuropathy. Cancers. 2021 Feb 12;13. (4). PMID: 33673136
  • Anderson JT, Huang KM, Lustberg MB, Sparreboom A, Hu S. Solute Carrier Transportome in Chemotherapy-Induced Adverse Drug Reactions. Reviews of physiology, biochemistry and pharmacology. 2022;183:177-215. PMID: 32761456
  • Jin Y, Li Y, Uddin ME, Sparreboom A, Hu S. Rapid quantification of vincristine in mouse plasma using ESI-LC-MS/MS: Application to pharmacokinetic studies. Journal of chromatography. B, Analytical technologies in the biomedical and life sciences. 2021 Apr 1;1168:122591. Epub 2021 Feb 21. PMID: 33684722
  • Fu Q, Sun X, Lustburg MB, Sparreboom A, Hu S. Predicting Paclitaxel Disposition in Humans With Whole-Body Physiologically-Based Pharmacokinetic Modeling. CPT: pharmacometrics & systems pharmacology. 2019 Dec;8(12):931-939. Epub 2019 Nov 16. PMID: 31671477
  • Uddin ME, Talebi Z, Chen S, Jin Y, Gibson AA, Noonan AM, Cheng X, Hu S, Sparreboom A. In Vitro and In Vivo Inhibition of MATE1 by Tyrosine Kinase Inhibitors. Pharmaceutics. 2021 Nov 25;13. (12). PMID: 34959286
  • Huang KM, Leblanc AF, Uddin ME, Kim JY, Chen M, Eisenmann ED, Gibson AA, Li Y, Hong KW, DiGiacomo D, Xia SH, Alberti P, Chiorazzi A, Housley SN, Cope TC, Sprowl JA, Wang J, Loprinzi CL, Noonan A, Lustberg MB, Cavaletti G, Pabla N, Hu S, Sparreboom A. Neuronal uptake transporters contribute to oxaliplatin neurotoxicity in mice. The Journal of clinical investigation. 2020 Sep 1;130(9):4601-4606. PMID: 32484793
  • Hayden ER, Chen M, Pasquariello KZ, Gibson AA, Petti JJ, Shen S, Qu J, Ong SS, Chen T, Jin Y, Uddin ME, Huang KM, Paz A, Sparreboom A, Hu S, Sprowl JA. Regulation of OATP1B1 Function by Tyrosine Kinase-mediated Phosphorylation. Clinical cancer research : an official journal of the American Association for Cancer Research. 2021 Aug 1;27(15):4301-4310. Epub 2021 Mar 4. PMID: 33664059
  • Li Y, Kazuki Y, Drabison T, Kobayashi K, Fujita KI, Xu Y, Jin Y, Ahmed E, Li J, Eisenmann ED, Baker SD, Cavaletti G, Sparreboom A, Hu S. Vincristine Disposition and Neurotoxicity Are Unchanged in Humanized CYP3A5 Mice. Drug metabolism and disposition: the biological fate of chemicals. 2024 Jan 9;52(2):80-85. PMID: 38071551

Clinical Trials

Study Name Clinical Trial ID
Nilotinib in Preventing Paclitaxel-Induced Peripheral Neuropathy in Patients With Stage I-III Breast Cancer NCT04205903