Preclinical profile of cabazitaxel
Open Access
- 1 October 2014
- journal article
- review article
- Published by Taylor & Francis Ltd in Drug Design, Development and Therapy
- Vol. 8, 1851-1867
- https://doi.org/10.2147/DDDT.S64940
Abstract
Preclinical profile of cabazitaxel Patricia Vrignaud,1 Dorothée Semiond,2 Veronique Benning,2 Eric Beys,2 Hervé Bouchard,3 Sunil Gupta4 1Sanofi Oncology, Vitry-sur-Seine, France; 2Sanofi DSAR, Alfortville, France; 3Sanofi LGCR, Vitry-sur-Seine, France; 4Sanofi Oncology, Cambridge, MA, USA First-generation taxanes have changed the treatment paradigm for a wide variety of cancers, but innate or acquired resistance frequently limits their use. Cabazitaxel is a novel second-generation taxane developed to overcome such resistance. In vitro, cabazitaxel showed similar antiproliferative activity to docetaxel in taxane-sensitive cell lines and markedly greater activity in cell lines resistant to taxanes. In vivo, cabazitaxel demonstrated excellent antitumor activity in a broad spectrum of docetaxel-sensitive tumor xenografts, including a castration-resistant prostate tumor xenograft, HID28, where cabazitaxel exhibited greater efficacy than docetaxel. Importantly, cabazitaxel was also active against tumors with innate or acquired resistance to docetaxel, suggesting therapeutic potential for patients progressing following taxane treatment and those with docetaxel-refractory tumors. In patients with tumors of the central nervous system (CNS), and in patients with pediatric tumors, therapeutic success with first-generation taxanes has been limited. Cabazitaxel demonstrated greater antitumor activity than docetaxel in xenograft models of CNS disease and pediatric tumors, suggesting potential clinical utility in these special patient populations. Based on therapeutic synergism observed in an in vivo tumor model, cabazitaxel is also being investigated clinically in combination with cisplatin. Nonclinical evaluation of the safety of cabazitaxel in a range of animal species showed largely reversible changes in the bone marrow, lymphoid system, gastrointestinal tract, and male reproductive system. Preclinical safety signals of cabazitaxel were consistent with the previously reported safety profiles of paclitaxel and docetaxel. Clinical observations with cabazitaxel were consistent with preclinical results, and cabazitaxel is indicated, in combination with prednisone, for the treatment of patients with hormone-refractory metastatic prostate cancer previously treated with docetaxel. In conclusion, the demonstrated activity of cabazitaxel in tumors with innate or acquired resistance to docetaxel, CNS tumors, and pediatric tumors made this agent a candidate for further clinical evaluation in a broader range of patient populations compared with first-generation taxanes. Keywords: XRP6258, CNS tumors, mCRPC, pediatric tumor, taxane resistance, xenograftKeywords
This publication has 62 references indexed in Scilit:
- Mechanism of Action of Antitumor Drugs that Interact with Microtubules and TubulinCurrent Medicinal Chemistry - Anti-Cancer Agents, 2012
- Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: long-term results of the TAX 324 randomised phase 3 trialThe Lancet Oncology, 2011
- Phase III Study of Docetaxel and Cisplatin Plus Fluorouracil Compared With Cisplatin and Fluorouracil As First-Line Therapy for Advanced Gastric Cancer: A Report of the V325 Study GroupJournal of Clinical Oncology, 2006
- Phase III randomised trial comparing paclitaxel/carboplatin with paclitaxel/cisplatin in patients with advanced non-small-cell lung cancer: a cooperative multinational trialAnnals of Oncology, 2002
- Structural Insights into Microtubule FunctionAnnual Review of Biophysics and Biophysical Chemistry, 2001
- Clinical Pharmacokinetics of DocetaxelClinical Pharmacokinetics, 1999
- Taxol-resistant epithelial ovarian tumors are associated with altered expression of specific beta-tubulin isotypes.JCI Insight, 1997
- Docetaxel (Taxotere®) a review of preclinical and clinical experience. Part IAnti-Cancer Drugs, 1995
- Preclinical evaluation of docetaxel (Taxotere).1995
- Taxol: A Novel Investigational Antimicrotubule AgentJNCI Journal of the National Cancer Institute, 1990