Abstract C90: HER2-targeted liposomal doxorubicin MM-302 has a favorable cardiosafety profile in preclinical models.

Abstract

Abstract Introduction: Anthracyclines have historically been the backbone of anticancer therapy for decades; however, the clinical observation of permanent cardiotoxicity has limited their broader use. In the HER2 positive breast cancer setting, the combination of trastuzumab with anthracyclines was associated with an unacceptable risk of clinical cardiotoxicity. This appears to be related to 1) doxorubicin-induced cardiomyocyte stress and 2) inability of the cardiomyocytes to respond to the stress due to the trastuzumab-related impairment of HER2 signaling. Encapsulation of doxorubicin into liposomes (Doxil®) has been associated with a reduced risk of doxorubicin-associated cardiotoxicity relative to free doxorubicin. MM-302 is a HER2-targeted liposomal doxorubicin-based agent designed to target doxorubicin to HER2-overexpressing cancer cells, while limiting uptake into non-target cells. Since HER2-mediated signaling plays an important role in cardiac repair, the purpose of this work was to support clinical development of MM-302 by investigating whether HER2-targeting of liposomal doxorubicin would adversely affect the cardiac safety profile relative to untargeted liposomal doxorubicin. Methods: MM-302, untargeted liposomal doxorubicin and free doxorubicin were compared for their uptake into HER2-overexpressing cancer cells and two models of human stem cell-derived cardiomyocytes. High-content microscopy was used to determine the effects of exposure to specific cellular targets in cardiomyocytes. Mouse biodistribution studies were used to assess the total and nuclear accumulation of doxorubicin in mouse cardiac tissue upon treatment with either MM-302, untargeted liposomes or free doxorubicin. Quantitative immunofluorescence was used to quantify the HER2 expression on human normal and diseased heart specimens. Kinetic computational modeling was applied to interpret study results and to make predictions on human heart exposure to doxorubicin based on the experimental mouse data. Results: Human stem cell-derived cardiomyocytes showed nuclear accumulation of doxorubicin followed by cell death upon free doxorubicin treatment but not upon MM-302 or untargeted liposomes treatment. Similarly, MM-302 resulted in a significantly lower nuclear accumulation of doxorubicin compared to free doxorubicin treatment in mouse cardiac tissue. HER2 expression levels on normal and diseased human heart tissue were shown to be ≤100,000 receptors/cell, in concordance with the HER2 levels on the stem cell-derived cardiomyocytes found in vitro. Computational modeling predicts liposomal encapsulation to significantly protect the human heart from exposure to doxorubicin, consistent with clinical findings. Conclusions: MM-302 is not taken up by human cardiomyocytes via HER2, but selectively increases doxorubicin delivery to human HER2-overexpressing tumor cells. MM-302 can potentially improve the clinical efficacy demonstrated by conventional anthracyclines and maintain the cardiac safety profile of untargeted liposomal doxorubicin in patients with HER2 overexpressing cancers. Clinical evaluation of this patient population is currently in Phase I. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C90.