C Patrick Reynolds1, Min H Kang1, John M Maris2, E Anders Kolb3, Richard Gorlick4, Jianrong Wu5, Raushan T Kurmasheva6, Peter J Houghton6, Malcolm A Smith7. 1. Texas Tech University Health Sciences Center, Lubbock, Texas. 2. Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine and Abramson Family Cancer Research Institute, Philadelphia, Pennsylvania. 3. A.I. duPont Hospital for Children, Wilmington, Delaware. 4. The Children's Hospital at Montefiore, Bronx, New York. 5. St. Jude Children's Research Hospital, Memphis, Tennessee. 6. Nationwide Children's Hospital, Columbus, Ohio. 7. Cancer Therapy Evaluation Program, NCI, Bethesda, Maryland.
Abstract
BACKGROUND: Although microtubule-destabilizing agents (principally vincristine) are in common use in pediatric oncology, the microtubule-stabilizing taxanes are uncommonly used to treat childhood cancers. Cabazitaxel has been reported to have activity superior to that of docetaxel in preclinical models of multidrug-resistant adult cancers, and it was active in patients who had progressed on or after docetaxel. The PPTP conducted a comparison of these two agents against the PPTP in vitro panel and against a limited panel of solid tumor xenografts. PROCEDURES: Cabazitaxel and docetaxel were tested against the PPTP in vitro cell line panel at concentrations from 0.01 to 0.1 μM and in vivo against a subset of the PPTP solid tumor xenograft models at a dose of 10 or 7.5 mg/kg on an every 4 days × 3 I.V. schedule. RESULTS: In vitro, both cabazitaxel and docetaxel had similar potency (median rIC50 0.47 nM and 0.88 nM, respectively) and a similar activity profile, with Ewing sarcoma cells being significantly more sensitive to both agents. In vitro sensitivity to docetaxel inversely correlated with mRNA expression for ABCB1, but the correlation with ABCB1 expression was weaker for cabazitaxel. In vivo cabazitaxel demonstrated significantly greater activity than docetaxel in five of 12 tumor models, inducing regressions in six models compared with three models for docetaxel. CONCLUSIONS: Cabazitaxel demonstrated superior activity compared to docetaxel. The lower cabazitaxel systemic exposure tolerated in humans compared to mice needs to be considered when extrapolating these results to the clinical setting.
BACKGROUND: Although microtubule-destabilizing agents (principally vincristine) are in common use in pediatric oncology, the microtubule-stabilizing taxanes are uncommonly used to treat childhood cancers. Cabazitaxel has been reported to have activity superior to that of docetaxel in preclinical models of multidrug-resistant adult cancers, and it was active in patients who had progressed on or after docetaxel. The PPTP conducted a comparison of these two agents against the PPTP in vitro panel and against a limited panel of solid tumor xenografts. PROCEDURES: Cabazitaxel and docetaxel were tested against the PPTP in vitro cell line panel at concentrations from 0.01 to 0.1 μM and in vivo against a subset of the PPTP solid tumor xenograft models at a dose of 10 or 7.5 mg/kg on an every 4 days × 3 I.V. schedule. RESULTS: In vitro, both cabazitaxel and docetaxel had similar potency (median rIC50 0.47 nM and 0.88 nM, respectively) and a similar activity profile, with Ewing sarcoma cells being significantly more sensitive to both agents. In vitro sensitivity to docetaxel inversely correlated with mRNA expression for ABCB1, but the correlation with ABCB1 expression was weaker for cabazitaxel. In vivo cabazitaxel demonstrated significantly greater activity than docetaxel in five of 12 tumor models, inducing regressions in six models compared with three models for docetaxel. CONCLUSIONS:Cabazitaxel demonstrated superior activity compared to docetaxel. The lower cabazitaxel systemic exposure tolerated in humans compared to mice needs to be considered when extrapolating these results to the clinical setting.
Authors: Jennifer K Peterson; Chandra Tucker; Edward Favours; Pamela J Cheshire; Jeremy Creech; Catherine A Billups; Richard Smykla; Francis Y F Lee; Peter J Houghton Journal: Clin Cancer Res Date: 2005-10-01 Impact factor: 12.531
Authors: Peter J Houghton; Christopher L Morton; Chandra Tucker; Debbie Payne; Edward Favours; Claire Cole; Richard Gorlick; E Anders Kolb; Wendong Zhang; Richard Lock; Hernan Carol; Mimi Tajbakhsh; C Patrick Reynolds; John M Maris; Joshua Courtright; Stephen T Keir; Henry S Friedman; Charles Stopford; Joseph Zeidner; Jianrong Wu; Tiebin Liu; Catherine A Billups; Javed Khan; Sherry Ansher; Jian Zhang; Malcolm A Smith Journal: Pediatr Blood Cancer Date: 2007-12 Impact factor: 3.167
Authors: C A Hurwitz; L C Strauss; J Kepner; C Kretschmar; M B Harris; H Friedman; L Kun; R Kadota Journal: J Pediatr Hematol Oncol Date: 2001 Jun-Jul Impact factor: 1.289
Authors: Renée de Leeuw; Lisa D Berman-Booty; Matthew J Schiewer; Stephen J Ciment; Robert B Den; Adam P Dicker; William K Kelly; Edouard J Trabulsi; Costas D Lallas; Leonard G Gomella; Karen E Knudsen Journal: Clin Cancer Res Date: 2015-02-15 Impact factor: 12.531
Authors: Alain C Mita; Louis J Denis; Eric K Rowinsky; Johann S Debono; Andrew D Goetz; Leonel Ochoa; Bahram Forouzesh; Muralidhar Beeram; Amita Patnaik; Kathleen Molpus; Dorothée Semiond; Michèle Besenval; Anthony W Tolcher Journal: Clin Cancer Res Date: 2009-01-15 Impact factor: 12.531
Authors: Richard Gorlick; E Anders Kolb; Stephen T Keir; John M Maris; Richard B Lock; Hernan Carol; C Patrick Reynolds; Min H Kang; Catherine A Billups; Jerry Collins; Dias Kurmashev; Raushan T Kurmasheva; Peter J Houghton; Malcolm A Smith Journal: Pediatr Blood Cancer Date: 2015-11-24 Impact factor: 3.167
Authors: Valerie B Sampson; Nancy S Vetter; Wendong Zhang; Pratima U Patil; Robert W Mason; Erika George; Richard Gorlick; Edward A Kolb Journal: Oncotarget Date: 2016-12-27