The anti-mitotic taxanes are one of the most important families of anticancer drugs that have broad anti-tumor activity and are widely used for a variety of human cancer types. However, the taxanes are limited by a number of serious pharmacological and toxicological effects, including dose limiting myelosuppression, neurotoxicity and serious hypersensitivity reactions. We are developing a unique delivery system for docetaxel, comprised of a PEGylated liposomal nanoparticle containing a prodrug of docetaxel to improve solubility, tolerability and increase efficacy through improved pharmacokinetics and biodistribution. In this study we evaluated the antitumor activity of MNK-010 on the growth of established human PC3 xenografts in male immunodeficient mice. This study tested the hypothesis that MNK-010 can provide greater efficacy than Taxotere (docetaxel) at equivalent maximum tolerated doses (MTD) in mice implanted with human PC3 tumor cells. Male nude mice bearing PC3 human prostate xenografts were given two or four intravenous (IV) doses of MNK-010, Taxotere or saline. Dosing intervals were twenty-one days for two cycles or every four days for four cycles. The doses of Taxotere and MNK-010 were based on maximum tolerated dose (MTD) or highest dose tested for a given dose interval. Tumor volume was measured twice per week using the Biopticon tumor imaging system and tumor volume data was analyzed to determine tumor growth delay and partial tumor regression. Survival analysis was conducted and median survival time determined. MNK-010 significantly (p <0.05) inhibited PC3 human tumor growth in nude mice at all dose regimens evaluated compared to saline and Taxotere treatment. MNK-010 delayed tumor growth up to 145 days, which was 59 days longer than Taxotere at its MTD. MNK-010 also partially regressed 90% - 100% of tumors in all dose groups. This antitumor activity contributed to achieving median survival of 177 days, which was 150 days longer than saline control and 80 days longer than Taxotere at its MTD. This study demonstrated that Mallinckrodt Pharmaceuticals’ PEGylated liposomal docetaxel prodrug nanoparticle MNK-010 is an active antitumor agent in the PC3 prostate xenograft and possess significantly greater antitumor activity compared to the standard of care Taxotere.
Citation Format: Richard M. Fitch, Jolette K. Wojdyla, James A. Blackledge, William D. McGhee. Anti-tumor activity of liposomal docetaxel prodrug MNK-010 on PC3 human prostate xenografts in mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4400. doi:10.1158/1538-7445.AM2015-4400