Abstract
As part of a longstanding collaborative project within the Bay Area Breast Cancer Translational Research Program (UCSF Breast SPORE), we have continued to use nude mouse human breast cancer xenograft models to test our hypothesis that more effective and less toxic delivery of potent anticancer drugs can be achieved using immunoliposomes (ILs), consisting of receptor-internalizing monoclonal antibody fragments covalently linked to drug-encapsulated long-circulating liposomes (Ls). Our lead agent, anti-HER2 immunoliposomes containing doxorubicin (anti-HER2 ILs-dox), now approaches clinical testing after preclinical evaluation and optimization against multiple breast cancer xenograft models expressing high (+3), moderate (+2), or low (+1) levels of the HER2/ErbB2 growth factor receptor. The enhanced in vivo therapeutic index achieved by anti-HER2 ILs-dox over immunoliposomes containing doxorubicin (+/- Herceptin/trastuzumab) or free doxorubicin was found to be due to the greater intracellular drug delivery achieved by receptor internalizing ILs. A new bioassay measuring HER2 receptor internalization by ILs and performed ex vivo on breast tumor cells or explants appears capable of identifying a subset of HER2 overexpressing breast tumors that may not respond to some HER2 receptor-targeted therapeutics. Other standard breast cancer chemotherapeutics (e.g. vinorelbine, camptothecins) and investigational agents (e.g. ellipticine, hydroxamic acid inhibitors of histone deacetylase) have been similarly encapsulated and evaluated against these tumor xenograft models, all showing enhanced therapeutic efficacy by the targeted ILs > nontargeted Ls > free drug. Likewise, the modular versatility of this drug delivery platform has been proven by linking drug-encapsulated Ls with an epidermal growth factor receptor (EGFR)/HER1 targeting/internalizing antibody and demonstrating the significantly improved efficacy and specificity of anti-EGFR ILs against EGFR overexpressing human breast cancer xenografts.
Highlights
The remarkable generation of scores of increasingly sophisticated mouse models of mammary cancer over the past two decades has provided tremendous insights into molecular derangements that can lead to cancer
We report that somatic mutations of p53 in mouse mammary epithelial cells lead to ERα-positive and ERαnegative tumors. p53 inactivation in pre-pubertal/pubertal mice, but not in adult mice, leads to the development of ERα-positive tumors, suggesting that developmental stages influence the availability of ERα-positive tumor origin cells
Genetic alterations commonly observed in human breast cancer including c-myc amplification and Her2/Neu/erbB2 activation were seen in these mouse tumors
Summary
Transgenic Oncogenesis Group, Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, Maryland, USA. The remarkable generation of scores of increasingly sophisticated mouse models of mammary cancer over the past two decades has provided tremendous insights into molecular derangements that can lead to cancer. The relationships of these models to human breast cancer, remain problematic. P53 inactivation in pre-pubertal/pubertal mice, but not in adult mice, leads to the development of ERα-positive tumors, suggesting that developmental stages influence the availability of ERα-positive tumor origin cells. These tumors have a high rate of metastasis that is independent of tumor latency. Since it is feasible to isolate ERα-positive epithelial cells from normal mammary glands and tumors, molecular mechanisms underlying ERα-positive and ERα-negative mammary carcinogenesis can be systematically addressed using this model
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