Abstract
HER-2 is a member of the EGF receptor family and is overexpressed in 20-30% of breast cancers. HER-2 overexpression causes increased expression of VEGF at both the RNA and protein levels. HER-2 and VEGF are therefore considered good targets for cancer treatment, which has led to the development of two humanized monoclonal antibodies (mAb) pertuzumab and bevacizumab. Although passive immunotherapy with these Abs are approved for treatment of advanced breast cancer, a number of concerns exist. Treatment is expensive, has a limited duration of action, and is usually accompanied by serious side effects. We hypothesized that therapy with conformational peptide mimics aimed at blocking receptor-ligand interaction is potentially safer with little toxicity, cheaper with a longer half-life, and has greater penetrating abilities than mAbs. We designed and synthesized peptides based on the binding of HER-2 with pertuzumab and VEGF with VEGFR2. We show that treatment with the peptide mimics induces potent anti-tumor responses in vitro as determined by cell viability, proliferation, and HER2 phosphorylation assays. We also demonstrate in a transplantable BALB/c mouse tumor model that treatment with the peptide mimics resulted in a greater delay in tumor growth and development. Similarly, treatment with the peptide mimics inhibited angiogenesis in vivo as assessed by a Matrigel plug assay. To address the problem of degradability of L-amino acid peptides in vivo, we synthesized the retro-inverso D-peptide mimics that resulted in higher efficacy in treatment. Our study shows that combination treatment with HER-2 and VEGF peptide mimics provides greater efficacy than individual treatments.
Highlights
Expression of HER-2 often show homogeneous, intense immunohistochemistry staining [6], signifying that HER-2-targeted therapy would target most cancer cells in a given patient
The up-regulation of HER-2 is associated with increased expression of vascular endothelial growth factor or VEGF at both the RNA and protein levels in human breast cancer cells, and exposure of HER-2-positive cells to trastuzumab significantly decreases VEGF expression [20]
A downstream adaptor protein of the HER-2 signaling pathway, has been identified as a critical switch for VEGF production [21] showing that VEGF is a downstream target of the HER-2 signaling pathway. This shows that the effects of HER-2 on tumor cell behavior may be mediated in part through stimulation of angiogenesis
Summary
Expression of HER-2 often show homogeneous, intense immunohistochemistry staining [6], signifying that HER-2-targeted therapy would target most cancer cells in a given patient. We have developed effective inhibitors of VEGF, VEGFR2 (see accompanying paper [73]) The latter objective was driven by the observation that HER-2 activation induces the expression of VEGF, which is a pro-angiogenic factor making blockade of angiogenesis an attractive and additional strategy to inhibit tumor growth, invasion, and metastasis. The basic hypothesis in the design of peptide mimics of VEGF and HER-2 is that many proteins exert their biological activity through relatively small regions of their folded surfaces This approach relies on the premise that the key residues of the binding epitope, in particular side-chain functional groups responsible for a significant portion of the binding affinity to a given receptor/ligand, may be transferred to a much smaller molecule with the contributions to binding largely intact [45]. The strategy for the retro-inverso (RI) modification of peptides relies on the synthesis of the sequence using D-amino acids in reverse order (from the N to C termini), such that the resulting peptide mimic has a reversal of the peptide backbone but a topochemical equivalence to the parent peptide in terms of side-chain orientation
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