Abstract
Abstract Background: Cabazitaxel (Jevtana®), a novel semi-synthetic taxane derived from 10-deacetyl baccatin III, was recently approved by the FDA and EMA for patients with metastatic hormone-refractory prostate cancer previously treated with docetaxel-based therapy. Cabazitaxel, which stabilizes in vitro microtubules as efficiently as docetaxel, was selected for clinical development for several reasons including: better anti-proliferative activity than docetaxel against chemotherapy resistant tumor cell lines (Bissery MC, AACR 2000), broad spectrum of in vivo anti-tumor activity docetaxel-sensitive tumors, and activity in tumor models in which docetaxel was either poorly active or inactive (Vrignaud P, AACR 2000). Interestingly, unlike docetaxel, cabazitaxel is able to cross the blood-brian barrier (Dykes DJ, AACR 2000) and has demonstrated activity in intracranial human glioblastomas. Further, in preclinical studies the combination of cabazitaxel and cisplatin exhibit therapeutic synergism (Vrignaud P, AACR 2011). Methods: In order to explore other therapeutic indications, the anti-tumor activity of cabazitaxel was evaluated in comparison to docetaxel in 3 different xenograft models of human pediatric tumors: RH-30 (rhabdomyosarcoma), TC-71 and SK-ES-1 (Ewing's tumors) in SCID female mice. Cabazitaxel and docetaxel were administered as single agents, IV in a dose response study (14.5, 9.0, 5.6 & 3.5 mg/kg), 5 days apart (e.g., days 14 and 18) after SC tumor implantation. Results: In the rhabdomysarcoma RH-30 model, cabazitaxel achieved 100% complete regression (CR) at the 2 highest dose levels and tumor regressions were also observed at the third dose level. Tumor free survivors (TFS on day 120) were observed only in the cabazitaxel treatment groups, 14.5 mg/kg (6/6) and at 9 mg/kg (5/6). In comparison, docetaxel induced CR only at the highest dose-level (14.5 mg/kg) tested. Against TC-71, cabazitaxel achieved 6/7 TFS at14.5 mg/kg and 9 mg/kg and 6/7 partial regressions (PR) were observed at 5.6 mg/kg. However, docetaxel only induced CR at the highest dose-level tested (14.5 mg/kg) with 1/7 TFS at day 120. Against SK-ES-1, cabazitaxel achieved 100% PR at 14.5, 9.0, 5.6 mg/kg, with 6/7 CR, leading to 3/7 TFS at the highest doses tested. In comparison, docetaxel induced 3/7 CR at the highest dose tested and no TFS were observed. Conclusion: Both cabazitaxel and docetaxel showed significant antitumor activity in all 3 human pediatric tumor xenografts; however, cabazitaxel demonstrated greater activity than docetaxel at comparable dose levels. Taken together, preclinical data with cabazitaxel including activity in brain tumors and therapeutic synergism with cisplatin, support its development in pediatric indications. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2775. doi:1538-7445.AM2012-2775
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