Abstract
Abstract MM-302 is a HER2-targeted liposomal doxorubicin formulation designed to target doxorubicin to HER2-overexpressing cancer cells while limiting uptake into non-target cells. The combination of doxorubicin with cyclophosphamide has been widely used in both the early- and late-stage breast cancer settings. Recent clinical trials have shown promising response rates to the combination of cyclophosphamide, pegylated liposomal doxorubicin (PLD) and trastuzumab in HER2-positive disease. The purpose of this study is to investigate the effects of cyclophosphamide on the tumor delivery of MM-302, and to evaluate the anti-tumor activity of this drug combination in preclinical models of breast cancer. Methods: Biodistribution studies were carried out in BT474-M3, SUM190, and MDA-MB-453 tumor-bearing mice to assess the delivery of MM-302, PLD and free doxorubicin as single agents or in combination with cyclophosphamide at different dosing schedules. The total doxorubicin within tumors was quantified by HPLC and, microscopically, by automated image analysis in order to determine the extent of doxorubicin-positive nuclei. Automated image analysis was also used to quantify tumor cell apoptosis, changes in tumor cell density, and induction of DNA-damage in response to drug treatment. Activity studies in BT474-M3 tumor-bearing mice were performed to evaluate the ability of the different dosing regimens to inhibit tumor growth. Results: Pre-dosing of tumors with cyclophosphamide significantly increased the delivery of MM-302 to tumors. The increase in delivery was tumor-specific, and the cyclophosphamide pre-dose had no effect on doxorubicin accumulation to non-target tissues such as heart or skin. Pre-treatment of tumors with cyclophosphamide also increased the delivery of PLD to tumors, but not of free doxorubicin. However, the increase in nuclear doxorubicin delivery via MM-302 compared to PLD was significantly higher in the HER2-positive breast cancer models analyzed. Histological analysis of the cyclophosphamide-treated tumors suggests that induction of tumor cell apoptosis and reduction of overall tumor cell density are among the mechanisms for improved MM-302 delivery and tumor cell response to doxorubicin in this preclinical model. Finally, treatment of BT474-M3 tumors with cyclophosphamide followed by MM-302 resulted in a significantly higher tumor growth inhibition compared to both single agents as well as compared to a MM-302 and cyclophosphamide co-injection regimen. Conclusions: Rational combination of MM-302 with cyclophosphamide is an active and tolerable combination in preclinical models that enhances the HER2-targeting properties of MM-302. This study suggests that cyclophosphamide may be a promising combination partner for MM-302 in clinical studies. Citation Format: Elena Geretti, Shannon C. Leonard, Daniel F. Gaddy, Nancy Dumont, Thomas J. Wickham, Bart S. Hendriks. Tumor priming with cyclophosphamide increases delivery and activity of Her2-targeted liposomal doxorubicin (MM-302) in preclinical models of breast cancer. [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 3271. doi:10.1158/1538-7445.AM2013-3271
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