Targeting mutant p53 protein and the tumor vasculature: an effective combination therapy for advanced breast tumors
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Breast cancer progression depends upon the elaboration of a vasculature sufficient for the nourishment of the developing tumor. Breast tumor cells frequently contain a mutant form of p53 (mtp53), a protein which promotes their survival. The aim of this study was to determine whether combination therapy targeting mtp53 and anionic phospholipids (AP) on tumor blood vessels might be an effective therapeutic strategy for suppressing advanced breast cancer. We examined the therapeutic effects, singly, or in combination, of p53 reactivation and induction of massive apoptosis (PRIMA-1), which reactivates mtp53 and induces tumor cell apoptosis, and 2aG4, a monoclonal antibody that disrupts tumor vasculature by targeting AP on the surface of tumor endothelial cells and causes antibody-dependent destruction of tumor blood vessels, leading to ischemia and tumor cell death. Xenografts from two tumor cell lines containing mtp53, BT-474 and HCC-1428, were grown in nude mice to provide models of advanced breast tumors. After treatment with PRIMA-1 and/or 2aG4, regressing tumors were analyzed for vascular endothelial growth factor (VEGF) expression, blood vessel loss, and apoptotic markers. Individual drug treatment led to partial suppression of breast cancer progression. In contrast, combined treatment with PRIMA-1 and 2aG4 was extremely effective in suppressing tumor growth in both models and completely eradicated approximately 30% of tumors in the BT-474 model. Importantly, no toxic effects were observed in any treatment group. Mechanistic studies determined that PRIMA-1 reactivated mtp53 and also exposed AP on the surface of tumor cells as determined by enhanced 2aG4 binding. Combination treatment led to significant induction of tumor cell apoptosis, loss of VEGF expression, as well as destruction of tumor blood vessels. Furthermore, combination treatment severely disrupted tumor blood vessel perfusion in both tumor models. The observed in vitro PRIMA-1-induced exposure of tumor epithelial cell AP might provide a target for 2aG4 and contribute to the increased effectiveness of such combination therapy in vivo. We conclude that the combined targeting of mtp53 and the tumor vasculature is a novel effective strategy for combating advanced breast tumors.
KeywordsBreast tumor growth Blood vessel targeting agent p53 p53 Reactivation and induction of massive apoptosis (PRIMA-1) Apoptosis Cell proliferation
We would like to acknowledge Peregrine Pharmaceuticals, Inc., for providing the anti-AP 2aG4. We would also like to thank Dr. Steve Yang, Jill Hansen, Vanessa Welbern, Jun Dong, and Linda Watkins for excellent technical assistance on this project. The authors also acknowledged the financial support from Department of Defense Breast Cancer Program Grant W81XWH-06-1-0646 (Y.L.), NIH Grants CA-86916 and R56-CA-86916, COR award and Research Funds from RADIL (University of Missouri), and in part by Susan G. Komen for the Cure Grants BCTR0600704 and PDF0600723.
Conflict of interest statement
P.E.T. is a consultant and holds a sponsored research agreement with Peregrine Pharmaceuticals, Inc., Tustin, CA. S.M.H. is the Zalk Missouri Professor of Tumor Angiogenesis.
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