Combined vaccination with HER-2 peptide followed by therapy with VEGF peptide mimics exerts effective anti-tumor and anti-angiogenic effects in vitro and in vivo

The Ohio State University
OncoImmunology (Impact Factor: 6.27). 10/2012; 1(7):1048-1060. DOI: 10.4161/onci.20708
Source: PubMed


Overexpression of HER-2 and VEGF plays a key role in the development and metastasis of several human cancers. Many FDA-approved therapies targeting both HER-2 (Trastuzumab, Herceptin) and VEGF (Bevacizumab, Avastin) are expensive, have unacceptable toxicities and are often associated with the development of resistance. Here, we evaluate the dual antitumor effects of combining designed particular HER-2 peptide vaccine with VEGF peptide mimics. In vitro, HER-2 phosphorylation and antibody-dependent cellular toxicity were used to validate whether combining HER-2- and VEGF-targeting therapies would be effective. Moreover, a two-pronged approach was tested in vivo: (1) active immunotherapy with conformational HER-2 B-cell epitope vaccines and (2) anti-angiogenic therapy with a peptide structured to mimic VEGF. A transplantable BALB/c mouse model challenged with TUBO cells was used to test the effects of the HER-2 peptide vaccine combined with VEGF peptide mimics. Tumor sections after treatment were stained for blood vessel density and actively dividing cells. Our results show that immunization with an HER-2 peptide epitope elicits high affinity HER-2 native antibodies that are effective in inhibiting tumor growth in vivo, an effect that is enhanced by VEGF peptide mimics. We demonstrate that the combination of HER-2 and VEGF peptides induces potent anti-tumor and anti-angiogenic responses.

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Available from: Pravin T Kaumaya, Oct 02, 2015
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    • "Studies from our laboratory have shown that a combined approach produces superior antitumor effects in vitro and in vivo when compared to single treatments (Foy et al., 2011). Immunization with our novel HER2 epitope vaccine, followed by VEGFR peptide mimic treatment, increased survival and significantly delayed tumor growth in mouse models of cancer (Foy et al., 2012b). We also evaluated a multi-modality approach in which low doses of chemotherapy (paclitaxel) combined with HER2 or VEGF peptide mimics improved response outcomes and minimized toxicity (Foy et al., 2012a). "
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    ABSTRACT: A promising new era of cancer therapeutics with agents that inhibit specific growth stimulatory pathways is finding a new niche in our armamentarium in the war against cancer. Targeted cancer therapeutics, including humanized monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs), are amongst the major treatment options for cancer today together with cytotoxic chemotherapies. Targeted therapies are more selective for cancer cells and improve the quality of life for cancer patients undergoing treatment. Many of these drugs have been approved by the FDA, and several more are being studied in clinical trials. Although development of targeted therapeutics has improved cancer treatment significantly, the harsh reality is that the "War on Cancer" still exists. Major challenges still exist with the currently marketed inhibitors, including limitations associated with mAbs and TKIs drug types, acquired mechanisms of drug resistance that cause patient relapse, and tumor heterogeneity. Today, there is an urgent need for the development of novel anti-tumor agents that are cheaper, stable, can selectively target cancer dependent pathways without affecting normal cells, and most importantly, avoid development of resistance mechanisms. Peptide mimics have the potential benefits of being highly selective, stable, cheap, and non-toxic. The focus of this review is to discuss the disadvantages associated with the use of monoclonal antibodies and tyrosine kinase inhibitors. A special emphasis will be placed on efforts taken in our laboratory to 1) design peptide vaccines and therapeutics that target cancer dependent pathways and 2) use a combination approach that will shut down alternative mechanisms that lead to resistance.
    Discovery medicine 03/2013; 15(82):166-76. · 3.63 Impact Factor
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    • "In recent years combination therapy is emerging as an important strategy to fight cancer as just one method may not be efficient enough to cure the disease completely or prevent recurrence [151]. In the hope of achieving synergistic effects, combinations of antiangiogenesis with traditional chemotherapy are currently being pursued in clinical trials [151–155]. For example, cilengitide was used in a phase I/IIa combination trial, which combined cilengitide with radiotherapy and temozolomide for newly diagnosed Glioblastoma patients resulting in better overall survival (OS) rates [152]. "
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    ABSTRACT: This paper discusses the role of peptides in cancer therapy with special emphasis on peptide drugs which are already approved and those in clinical trials. The potential of peptides in cancer treatment is evident from a variety of different strategies that are available to address the progression of tumor growth and propagation of the disease. Use of peptides that can directly target cancer cells without affecting normal cells (targeted therapy) is evolving as an alternate strategy to conventional chemotherapy. Peptide can be utilized directly as a cytotoxic agent through various mechanisms or can act as a carrier of cytotoxic agents and radioisotopes by specifically targeting cancer cells. Peptide-based hormonal therapy has been extensively studied and utilized for the treatment of breast and prostate cancers. Tremendous amount of clinical data is currently available attesting to the efficiency of peptide-based cancer vaccines. Combination therapy is emerging as an important strategy to achieve synergistic effects in fighting cancer as a single method alone may not be efficient enough to yield positive results. Combining immunotherapy with conventional therapies such as radiation and chemotherapy or combining an anticancer peptide with a nonpeptidic cytotoxic drug is an example of this emerging field.
    12/2012; 2012(1):967347. DOI:10.1155/2012/967347
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    ABSTRACT: The ErbB family (HER-1, HER-2, HER-3 and HER-4) of receptor tyrosine kinases has been the focus of cancer immunotherapeutic strategies while antiangiogenic therapies have focused on VEGF and its receptors VEGFR-1 and VEGFR-2. Agents targeting receptor tyrosine kinases in oncology include therapeutic antibodies to receptor tyrosine kinase ligands or the receptors themselves, and small-molecule inhibitors. Many of the US FDA-approved therapies targeting HER-2 and VEGF exhibit unacceptable toxicities, and show problems of efficacy, development of resistance and unacceptable safety profiles that continue to hamper their clinical progress. The combination of different peptide vaccines and peptidomimetics targeting specific molecular pathways that are dysregulated in tumors may potentiate anticancer immune responses, bypass immune tolerance and circumvent resistance mechanisms. The focus of this review is to discuss efforts in our laboratory spanning two decades of rationally developing peptide vaccines and therapeutics for breast cancer. This review highlights the prospective benefit of a new, untapped category of therapies biologically targeted to EGF receptor (HER-1), HER-2 and VEGF with potential peptide 'blockbusters' that could lay the foundation of a new paradigm in cancer immunotherapy by creating clinical breakthroughs for safe and efficacious cancer cures.
    Future Oncology 08/2012; 8(8):961-87. DOI:10.2217/fon.12.95 · 2.48 Impact Factor
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