Abstract 316: Cabazitaxel antitumor activity in docetaxel-resistant patient-derived prostate cancer xenograft models.
Authors: de Morree Ellen S. , de Ridder Corrina M.A. , Burger Herman , Wiemer Erik A.C. , Mathijssen Ron H.J. , de Wit Ronald , van Weerden Wytske M. 
Published: August 2014

Introduction: The first line of chemotherapy for castration resistant prostate cancer (CRPC) patients is docetaxel treatment. Continued treatment after progression on docetaxel with cabazitaxel can be very strenuous for patients. Clearly, selection of patients that will benefit from either docetaxel or cabazitaxel treatment would be an essential asset to the management of CRPC. Therefore docetaxel-resistant, CRPC xenografts PC339-DOC and PC346C-DOC were developed. These xenografts were tested for sensitivity to cabazitaxel as an initial step to develop a biomarker gene expression profile of docetaxel resistance and cabazitaxel sensitivity in CRPC.

Materials and Methods: PC339 (low sensitivity to docetaxel, log cell kill 0.7) and PC346C (moderate sensitivity to docetaxel, log cell kill 1.0) bearing mice were treated with bolus injections of docetaxel (33 mg/kg) every two weeks until the tumor became resistant. Cabazitaxel efficacy was tested in the resistant xenografts by treating PC339-DOC and PC346C-DOC bearing mice with a single bolus injection cabazitaxel (33 mg/kg). Body weight and tumor volume (TV) were monitored up to 160 days post-treatment. Log cell kill was calculated as measure of antitumor activity, taken into account the tumor growth delay induced by the treatment and the tumor doubling time of the tumor (log cell kill= tumor growth delay / tumor doubling time x 3,32). Log cell kill values of &lt; 0.7 reflect no antitumor activity. Importantly, both naïve and resistant xenografts are lacking expression of docetaxel transporter P-glycoprotein (P-gp/ABCB1/MDR1).

Results: PC339-DOC was generated within 4 months after start of docetaxel treatment suggesting some intrinsic resistance against docetaxel. In contrast, PC346C-DOC could be classified as acquired resistance as it took more than one year to develop docetaxel resistance in the naïve PC346C. Cabazitaxel was highly active in PC339-DOC, causing complete regression in 4 out of 5 mice (log cell kill &gt; 2.8) while cabazitaxel lacked antitumor activity in PC346C-DOC (log cell kill 0.20).

Conclusion: Cabazitaxel was highly active in a docetaxel-resistant PC339DOC xenograft. Low antitumor activity in PC346C-DOC suggests different mechanisms of resistance in both resistant models and potential cross-resistance between taxanes. The differences between PC339-DOC and PC346C-DOC will allow the development of a biomarker profile to specifically select CRPC patients that could benefit from continued treatment with taxanes.

Citation Format: Ellen S. de Morree, Corrina M.A. de Ridder, Herman Burger, Erik A.C. Wiemer, Ron H.J. Mathijssen, Ronald de Wit, Wytske M. van Weerden. Cabazitaxel antitumor activity in docetaxel-resistant patient-derived prostate cancer xenograft models. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 316. doi:10.1158/1538-7445.AM2013-316