Combination Immunotherapy with Her-2/neu and Vegf Peptide Mimics in Both Transgenic and Transplantable Mouse Models of Human Breast Cancer

Her-2/neu (ErbB2) is a member of the epidermal growth factor family of receptors and is overexpressed in about 30% of breast cancers. Targeting this receptor is a very attractive strategy for antitumor therapy using both peptides and monoclonal antibodies. Trastuzumab and Pertuzumab are humanized monoclonal antibodies that both target the extracellular domain of the Her-2 receptor. Great limitations still exists with these treatments due to their high cost and limited duration of action, thereby necessitating repeated administration of the drugs. The overexpression of Her-2 leads to overexpression of another protein known as vascular endothelial growth factor (VEGF) which turns on the angiogenic switch aimed at causing increased blood flow and oxygen to the tumors. Without an increase in blood flow, the tumors cannot increase in size, hence angiogenesis is required for tumor growth and metastasis. VEGF is known to interact with one of its receptors VEGFR-2 before it can stimulate angiogenesis. The disruption of this interaction is considered another attractive target forcancer therapy and monoclonal antibodies like Bevacizumab have been developed to prevent this interaction. This work is mainly centered on the use of peptides for cancer treatment that are cost effective, specific and non-toxic to target both Her-2 and VEGF. Treatment with conformational B-cell epitopes affords the possibility of generating an enduring immune response and eliciting protein reactive high affinity peptide antibodies. We have designed conformational peptides of the pertuzumab epitope and also peptides that mimic the VEGF binding sites. With the use of in vitro assays and two in vivo tumor models (transgenic and transplantable), we have shown that combination treatment aimed at targeting the HER-2/neu and VEGF signaling pathways produce additive effects with no problems of cardiotoxicity. We also showed that combining these peptide mimics with standard chemotherapy produces increase survival free rates and a decrease in tumor growth and development. Combination immunotherapy with antibodies raised against these peptide vaccines was also able to additively inhibit tumor growth in vitro as demonstrated using Her-2 signaling processes like proliferation and phosphorylation of the HER-2 receptor.