Peptide vaccines and peptidomimetics targeting HER and VEGF proteins may offer a potentially new paradigm in cancer immunotherapy

Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

References

• 1  Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat. Rev. Cancer5,341–354 (2005).
  Medline CASGoogle Scholar
• 2  Kim JY, Sun Q, Oglesbee M, Yoon SO. The role of ErbB2 signaling in the onset of terminal differentiation of oligodendrocytes in vivo. J. Neurosci.23,5561–5571 (2003).
  Medline CASGoogle Scholar
• 3  Vinter-Jensen L. Pharmacological effects of epidermal growth factor (EGF) with focus on the urinary and gastrointestinal tracts. APMIS Suppl.93,1–42 (1999).
  Medline CASGoogle Scholar
• 4  Arteaga CL, Moulder SL, Yakes FM. HER (erbB) tyrosine kinase inhibitors in the treatment of breast cancer. Semin. Oncol.29,4–10 (2002).
  Medline CASGoogle Scholar
• 5  Barbacci EG, Guarino BC, Stroh JG et al. The structural basis for the specificity of epidermal growth factor and heregulin binding. J. Biol. Chem.270,9585–9589 (1995).
  Medline CASGoogle Scholar
• 6  Tzahar E, Waterman H, Chen X et al. A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor. Mol. Cell. Biol.16,5276–5287 (1996).
  Medline CASGoogle Scholar
• 7  Graus-Porta D, Beerli RR, Daly JM, Hynes NE. ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling. EMBO J.16,1647–1655 (1997).
  Medline CASGoogle Scholar
• 8  Beerli RR, Graus-Porta D, Woods-Cook K, Chen X, Yarden Y, Hynes NE. Neu differentiation factor activation of ErbB-3 and ErbB-4 is cell specific and displays a differential requirement for ErbB-2. Mol. Cell. Biol.15,6496–6505 (1995).
  Medline CASGoogle Scholar
• 9  Graus-Porta D, Beerli RR, Hynes NE. Single-chain antibody-mediated intracellular retention of ErbB-2 impairs Neu differentiation factor and epidermal growth factor signaling. Mol. Cell. Biol.15,1182–1191 (1995).
  Medline CASGoogle Scholar
• 10  Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J.19,3159–3167 (2000).
  Medline CASGoogle Scholar
• 11  Hynes NE, Stern DF. The biology of erbB-2/neu/HER-2 and its role in cancer. Biochim. Biophys. Acta1198,165–184 (1994).
  MedlineGoogle Scholar
• 12  Scholl S, Beuzeboc P, Pouillart P. Targeting HER2 in other tumor types. Ann. Oncol.12(Suppl. 1),S81–S87 (2001).
  MedlineGoogle Scholar
• 13  Colomer R, Shamon LA, Tsai MS, Lupu R. Herceptin: from the bench to the clinic. Cancer Invest.19,49–56 (2001).
  Medline CASGoogle Scholar
• 14  Press MF, Cordon-Cardo C, Slamon DJ. Expression of the HER-2/neu proto-oncogene in normal human adult and fetal tissues. Oncogene5,953–962 (1990).
  Medline CASGoogle Scholar
• 15  Paik S, Hazan R, Fisher ER et al. Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project: prognostic significance of erbB-2 protein overexpression in primary breast cancer. J. Clin. Oncol.8,103–112 (1990).
  Medline CASGoogle Scholar
• 16  Niehans GA, Singleton TP, Dykoski D, Kiang DT. Stability of HER-2/neu expression over time and at multiple metastatic sites. J. Natl Cancer Inst.85,1230–1235 (1993).
  Medline CASGoogle Scholar
• 17  Mimura K, Kono K, Hanawa M et al. Frequencies of HER-2/neu expression and gene amplification in patients with oesophageal squamous cell carcinoma. Br. J. Cancer92,1253–1260 (2005).
  Medline CASGoogle Scholar
• 18  Morrison C, Zanagnolo V, Ramirez N et al. HER-2 is an independent prognostic factor in endometrial cancer: association with outcome in a large cohort of surgically staged patients. J. Clin. Oncol.24,2376–2385 (2006).
  Medline CASGoogle Scholar
• 19  Yano T, Doi T, Ohtsu A et al. Comparison of HER2 gene amplification assessed by fluorescence in situ hybridization and HER2 protein expression assessed by immunohistochemistry in gastric cancer. Oncol. Rep.15,65–71 (2006).
  MedlineGoogle Scholar
• 20  Cirisano FD, Karlan BY. The role of the HER-2/neu oncogene in gynecologic cancers. J. Soc. Gynecol. Invest.3,99–105 (1996).
  Medline CASGoogle Scholar
• 21  Berchuck A, Rodriguez G, Kinney RB et al. Overexpression of HER-2/neu in endometrial cancer is associated with advanced stage disease. Am. J. Obstet. Gynecol.164,15–21 (1991).
  Medline CASGoogle Scholar
• 22  Kern JA, Schwartz DA, Nordberg JE et al. p185neu expression in human lung adenocarcinomas predicts shortened survival. Cancer Res.50,5184–5187 (1990).
  Medline CASGoogle Scholar
• 23  Carter P, Presta L, Gorman CM et al. Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc. Natl Acad. Sci. USA89,4285–4289 (1992).
  Medline CASGoogle Scholar
• 24  Nahta R, Yu D, Hung MC, Hortobagyi GN, Esteva FJ. Mechanisms of disease: understanding resistance to HER2-targeted therapy in human breast cancer. Nat. Clin. Pract. Oncol.3,269–280 (2006).▪▪ Outlines the reasons for the development of resistance to HER-2-targeted drugs such as trastuzumab because of activation of multiple receptor pathways that include HER-2-related receptors or non-HER receptors such as the IGF-1 receptor.
  Medline CASGoogle Scholar
• 25  Agus DB, Akita RW, Fox WD et al. Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell2,127–137 (2002).
  Medline CASGoogle Scholar
• 26  Agus DB, Gordon MS, Taylor C et al. Phase I clinical study of pertuzumab, a novel HER dimerization inhibitor, in patients with advanced cancer. J. Clin. Oncol.23(11),2534–2543 (2005).
  Medline CASGoogle Scholar
• 27  Nahta R, Hung MC, Esteva FJ. The HER-2-targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. Cancer Res.64,2343–2346 (2004).
  Medline CASGoogle Scholar
• 28  Scheuer W, Friess T, Burtscher H, Bossenmaier B, Endl J, Hasmann M. Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Res.24,9330–9336 (2009).
  Google Scholar
• 29  Walshe JM, Denduluri N, Berman AW, Rosing DR, Swain SM. A Phase II trial with trastuzumab and pertuzumab in patients with HER2-overexpressed locally advanced and metastatic breast cancer. Clin. Breast Cancer6,535–539 (2006).
  Medline CASGoogle Scholar
• 30  Heymach JV, Nilsson M, Blumenschein G, Papadimitrakopoulou V, Herbst R. Epidermal growth factor receptor inhibitors in development for the treatment of non-small cell lung cancer. Clin. Cancer Res.12,4441S–4445S (2006).
  Medline CASGoogle Scholar
• 31  Gordon MS, Matei D, Aghajanian C et al. Clinical activity of pertuzumab (rhuMAb 2C4), a HER dimerization inhibitor, in advanced ovarian cancer: potential predictive relationship with tumor HER2 activation status. J. Clin. Oncol.24,4324–4332 (2006).
  Medline CASGoogle Scholar
• 32  Agus DB, Sweeney CJ, Morris MJ et al. Efficacy and safety of single-agent pertuzumab (rhuMAb 2C4), a human epidermal growth factor receptor dimerization inhibitor, in castration-resistant prostate cancer after progression from taxane-based therapy. J. Clin. Oncol.25,675–681 (2007).
  Medline CASGoogle Scholar
• 33  Chow NH, Liu HS, Lee EI et al. Significance of urinary epidermal growth factor and its receptor expression in human bladder cancer. Anticancer Res.17,1293–1296 (1997).
  Medline CASGoogle Scholar
• 34  Angelucci A. Targeting ERBB receptors to inhibit metastasis: old hopes and new certainties. Curr. Cancer Drug Targets9,1–18 (2009).
  Medline CASGoogle Scholar
• 35  Patan S. Vasculogenesis and angiogenesis as mechanisms of vascular network formation, growth and remodeling. J. Neurooncol.50,1–15 (2000).
  Medline CASGoogle Scholar
• 36  Mendelsohn J. Targeting the epidermal growth factor receptor for cancer therapy. J. Clin. Oncol.20,1S–13S (2002).▪ Describes the role played by EGF receptor (EGFR) in different types of cancer and the efforts that have been made to target EGFR in the clinic. The article illustrates the central role played by EGFR in tumorigenesis and how it can be upregulated when other HER family receptors are targeted.
  Medline CASGoogle Scholar
• 37  Johnston JB, Navaratnam S, Pitz MW et al. Targeting the EGFR pathway for cancer therapy. Curr. Med. Chem.13,3483–3492 (2006).
  Medline CASGoogle Scholar
• 38  Grothey A. Recognizing and managing toxicities of molecular targeted therapies for colorectal cancer. Oncol. (Williston Park)20,21–28 (2006).
  MedlineGoogle Scholar
• 39  Schaefer G, Haber L, Crocker LM et al. A two-in-one antibody against HER3 and EGFR has superior inhibitory activity compared with monospecific antibodies. Cancer Cell20,472–486 (2011).
  Medline CASGoogle Scholar
• 40  Sutherland RL. Endocrine resistance in breast cancer: new roles for ErbB3 and ErbB4. Breast Cancer Res.13(3),106 (2011).▪ Discusses the roles played by ErbB-3 and ErbB-4 in the development of resistance, which is a major limitation to the successful treatment of estrogen receptor-positive (ER+) breast cancer, and the EGF receptor and ErbB-2 receptor tyrosine kinases are involved in this process. It summarizes recent studies that now implicate the other two ErbB family members, ErbB-3 and -4, in the resistance and metastasis of cancer cells.
  MedlineGoogle Scholar
• 41  Brennan PJ, Kumagai T, Berezov A, Murali R, Greene MI. HER2/Neu: mechanisms of dimerization/oligomerization. Oncogene21,328 (2002).
  Medline CASGoogle Scholar
• 42  Stern DF. ERBB3/HER3 and ERBB2/HER2 duet in mammary development and breast cancer. J. Mammary Gland Biol.13,215–223 (2008).
  MedlineGoogle Scholar
• 43  Srinivasan R, Leverton KE, Sheldon H, Hurst HC, Sarraf C, Gullick WJ. Intracellular expression of the truncated extracellular domain of c-erbB-3/HER3. Cell. Signal.13,321–330 (2001).
  Medline CASGoogle Scholar
• 44  Baselga J, Swain SM. Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat. Rev. Cancer9,463–475 (2009).
  Medline CASGoogle Scholar
• 45  Eisenberg D, Singer E, Landgraf R, Horan T, Slamon D. Identification of a heregulin binding site in HER3 extracellular domain. J. Biol. Chem.276,44266–44274 (2001).
  MedlineGoogle Scholar
• 46  Sliwkowski MX, Lee-Hoeflich ST, Crocker L et al. A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res.68,5878–5887 (2008).▪ Provides significant evidence that HER-3 plays a central role in HER-2-amplified breast cancers and that targeting just HER-2 results in the stimulation of HER-3 signaling mechanisms as an escape pathway to HER-2 targeting agents. The paper concludes that a combined approach targeting both HER-2 and HER-3 is a promising strategy.
  MedlineGoogle Scholar
• 47  Pinkas-Kramarski R, Soussan L, Waterman H et al. Diversification of Neu differentiation factor and epidermal growth factor signaling by combinatorial receptor interactions. EMBO J.15,2452–2467 (1996).
  Medline CASGoogle Scholar
• 48  Alimandi M, Romano A, Curia MC et al. Cooperative signaling of Erbb3 and Erbb2 in neoplastic transformation and human mammary carcinomas. Oncogene10,1813–1821 (1995).
  Medline CASGoogle Scholar
• 49  Garrett JT, Olivares MG, Rinehart C et al. Transcriptional and posttranslational up-regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase. Proc. Natl Acad. Sci. USA108(12),5021–5026 (2011).
  Medline CASGoogle Scholar
• 50  Lee-Hoeflich ST, Crocker L, Yao E et al. A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res.68,5878–5887 (2008).
  Medline CASGoogle Scholar
• 51  Engelman JA, Schoeberl B, Faber AC et al. An ErbB3 antibody, MM-121, is active in cancers with ligand-dependent activation. Cancer Res.70,2485–2494 (2010).
  MedlineGoogle Scholar
• 52  Hynes NE, Holbro T, Beerli RR, Maurer F, Koziczak M, Barbas CF. The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc. Natl Acad. Sci. USA100,8933–8938 (2003).
  MedlineGoogle Scholar
• 53  Sithanandam G, Anderson LM. The ERBB3 receptor in cancer and cancer gene therapy. Cancer Gene Ther.15,413–448 (2008).
  Medline CASGoogle Scholar
• 54  Tzahar E, Waterman H, Chen XM et al. A hierarchical network of interreceptor interactions determines signal transduction by neu differentiation factor/neuregulin and epidermal growth factor. Mol. Cell. Biol.16,5276–5287 (1996).
  Medline CASGoogle Scholar
• 55  Croce CM, Iorio MV, Casalini P et al. microRNA-205 regulates HER3 in human breast cancer. Cancer Res.69,2195–2200 (2009).
  MedlineGoogle Scholar
• 56  Liu BL, Ordonez-Ercan D, Fan ZY, Edgerton SM, Yang XH, Thor AD. Downregulation of erbB3 abrogates erbB2-mediated tamoxifen resistance in breast cancer cells. Int. J. Cancer120,1874–1882 (2007).
  Medline CASGoogle Scholar
• 57  Alaoui-Jamali MA, Yen L, Benlimame N et al. Differential regulation of tumor angiogenesis by distinct ErbB homo- and heterodimers. Mol. Biol. Cell13,4029–4044 (2002).
  MedlineGoogle Scholar
• 58  Rajkumar T, Stamp GWH, Pandha HS, Waxman J, Gullick WJ. Expression of the type 1 tyrosine kinase growth factor receptors EGF receptor, c-erbB2 and c-erbB3 in bladder cancer. J. Pathol.179,381–385 (1996).
  Medline CASGoogle Scholar
• 59  Moasser MM, Sergina NV. The HER family and cancer: emerging molecular mechanisms and therapeutic targets. Trends Mol. Med.13,527–534 (2007).
  MedlineGoogle Scholar
• 60  Moasser MM, Sergina NV, Rausch M et al. Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature445,437–441 (2007).
  MedlineGoogle Scholar
• 61  Engelman JA, Zejnullahu K, Mitsudomi T et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science316,1039–1043 (2007).
  Medline CASGoogle Scholar
• 62  Amler L, Makhija S, Januario T et al. Downregulation of HER3 may predict clinical benefit in ovarian cancer from pertuzumab, a HER2 dimerization-inhibiting antibody. Presented at: ASCO-NCI-EORTC Annual Meeting on Molecular Markers in Cancer. Abstract 25 (2008).
  Google Scholar
• 63  Jordan VC, Osipo C, Meeke K et al. Role for HER2/neu and HER3 in fulvestrant-resistant breast cancer. Int. J. Oncol.30,509–520 (2007).
  MedlineGoogle Scholar
• 64  Lykkesfeldt AE, Frogne T, Benjaminsen RV et al. Activation of ErbB3, EGFR and Erk is essential for growth of human breast cancer cell lines with acquired resistance to fulvestrant. Breast Cancer Res. Treat.114,263–275 (2009).
  MedlineGoogle Scholar
• 65  Arteaga CL, Miller TW, Perez-Torres M et al. Loss of phosphatase and tensin homologue deleted on chromosome 10 engages ErbB3 and insulin-like growth factor-I receptor signaling to promote antiestrogen resistance in breast cancer. Cancer Res.69,4192–4201 (2009).
  MedlineGoogle Scholar
• 66  Elenius K, Erjala K, Sundvall M et al. Signaling via ErbB2 and ErbB3 associates with resistance and epidermal growth factor receptor (EGFR) amplification with sensitivity to EGFR inhibitor gefitinib in head and neck squamous cell carcinoma cells. Clin. Cancer Res.12,4103–4111 (2006).
  MedlineGoogle Scholar
• 67  Hamburger AW, Zhang YX, Linn D et al. EBP1, an ErbB3-binding cancer and implicated in protein, is decreased in prostate hormone resistance. Mol. Cancer Ther.7,3176–3186 (2008).
  MedlineGoogle Scholar
• 68  Weber J. Peptide vaccines for cancer. Cancer Invest.20,208–221 (2002).
  Medline CASGoogle Scholar
• 69  Buteau C, Markovic SN, Celis E. Challenges in the development of effective peptide vaccines for cancer. Mayo. Clin. Proc.77,339–349 (2002).
  Medline CASGoogle Scholar
• 70  Lazoura E, Apostolopoulos V. Rational peptide-based vaccine design for cancer immunotherapeutic applications. Curr. Med. Chem.12,629–639 (2005).
  Medline CASGoogle Scholar
• 71  Disis ML, Calenoff E, McLaughlin G et al. Existent T-cell and antibody immunity to HER-2/neu protein in patients with breast cancer. Cancer Res.54,16–20 (1994).
  Medline CASGoogle Scholar
• 72  Disis ML, Pupa SM, Gralow JR, Dittadi R, Menard S, Cheever MA. High-titer HER-2/neu protein-specific antibody can be detected in patients with early-stage breast cancer. J. Clin. Oncol.15,3363–3367 (1997).
  Medline CASGoogle Scholar
• 73  Disis ML, Gralow JR, Bernhard H, Hand SL, Rubin WD, Cheever MA. Peptide-based, but not whole protein, vaccines elicit immunity to HER-2/neu, oncogenic self-protein. J. Immunol.156,3151–3158 (1996).
  Medline CASGoogle Scholar
• 74  Disis ML, Grabstein KH, Sleath PR, Cheever MA. Generation of immunity to the HER-2/neu oncogenic protein in patients with breast and ovarian cancer using a peptide-based vaccine. Clin. Cancer Res.5,1289–1297 (1999).
  Medline CASGoogle Scholar
• 75  Fisk B, Blevins TL, Wharton JT, Ioannides CG. Identification of an immunodominant peptide of HER-2/neu protooncogene recognized by ovarian tumor-specific cytotoxic T lymphocyte lines. J. Exp. Med.181,2109–2117 (1995).
  Medline CASGoogle Scholar
• 76  Baxevanis CN, Voutsas IF, Tsitsilonis OE, Gritzapis AD, Sotiriadou R, Papamichail M. Tumor-specific CD4⁺ T lymphocytes from cancer patients are required for optimal induction of cytotoxic T cells against the autologous tumor. J. Immunol.164,3902–3912 (2000).
  Medline CASGoogle Scholar
• 77  Lindencrona JA, Preiss S, Kammertoens T et al. CD4⁺ T cell-mediated HER-2/neu-specific tumor rejection in the absence of B cells. Int. J. Cancer109,259–264 (2004).
  Medline CASGoogle Scholar
• 78  Tuttle TM, Anderson BW, Thompson WE et al. Proliferative and cytokine responses to class II HER-2/neu-associated peptides in breast cancer patients. Clin. Cancer Res.4,2015–2024 (1998).
  Medline CASGoogle Scholar
• 79  Kobayashi H, Wood M, Song Y, Appella E, Celis E. Defining promiscuous MHC class II helper T-cell epitopes for the HER2/neu tumor antigen. Cancer Res.60,5228–5236 (2000).
  Medline CASGoogle Scholar
• 80  Sotiriadou R, Perez SA, Gritzapis AD et al. Peptide HER2(776-788) represents a naturally processed broad MHC class II-restricted T cell epitope. Br. J. Cancer85,1527–1534 (2001).
  Medline CASGoogle Scholar
• 81  Perez SA, Sotiropoulou PA, Sotiriadou NN et al. HER-2/neu-derived peptide 884-899 is expressed by human breast, colorectal and pancreatic adenocarcinomas and is recognized by in-vitro-induced specific CD4(+) T cell clones. Cancer Immunol. Immunother.50,615–624 (2002).
  Medline CASGoogle Scholar
• 82  Fisk B, Hudson JM, Kavanagh J et al. Existent proliferative responses of peripheral blood mononuclear cells from healthy donors and ovarian cancer patients to HER-2 peptides. Anticancer Res.17,45–53 (1997).
  Medline CASGoogle Scholar
• 83  Mittendorf EA, Clifton GT, Holmes JP et al. Clinical trial results of the HER-2/neu (E75) vaccine to prevent breast cancer recurrence in high-risk patients: from US Military Cancer Institute Clinical Trials Group Study I-01 and I-02. Cancer118(10),2594–2602 (2012).
  Medline CASGoogle Scholar
• 84  Sears AK, Perez SA, Clifton GT et al. AE37: a novel T-cell-eliciting vaccine for breast cancer. Expert Opin Biol. Ther.11,1543–1550 (2011).
  Medline CASGoogle Scholar
• 85  Mittendorf EA, Storrer CE, Foley RJ et al. Evaluation of the HER2/neu-derived peptide GP2 for use in a peptide-based breast cancer vaccine trial. Cancer106,2309–2317 (2006).
  Medline CASGoogle Scholar
• 86  Clive KS, Tyler JA, Clifton GT et al. The GP2 peptide: a HER2/neu-based breast cancer vaccine. J. Surg. Oncol.105,452–458 (2012).
  Medline CASGoogle Scholar
• 87  Reilly RT, Gottlieb MB, Ercolini AM et al. HER-2/neu is a tumor rejection target in tolerized HER-2/neu transgenic mice. Cancer Res.60,3569–3576 (2000).
  Medline CASGoogle Scholar
• 88  Nanni P, Nicoletti G, De Giovanni C et al. Combined allogeneic tumor cell vaccination and systemic interleukin 12 prevents mammary carcinogenesis in HER-2/neu transgenic mice. J. Exp. Med.194,1195–1205 (2001).
  Medline CASGoogle Scholar
• 89  Cefai D, Morrison BW, Sckell A et al. Targeting HER-2/neu for active-specific immunotherapy in a mouse model of spontaneous breast cancer. Int. J. Cancer83,393–400 (1999).
  Medline CASGoogle Scholar
• 90  Dela Cruz JS, Lau SY, Ramirez EM et al. Protein vaccination with the HER2/neu extracellular domain plus anti-HER2/neu antibody-cytokine fusion proteins induces a protective anti-HER2/neu immune response in mice. Vaccine21,1317–1326 (2003).
  Medline CASGoogle Scholar
• 91  Amici A, Venanzi FM, Concetti A. Genetic immunization against neu/erbB2 transgenic breast cancer. Cancer Immunol. Immunother.47,183–190 (1998).
  Medline CASGoogle Scholar
• 92  Piechocki MP, Pilon SA, Wei WZ. Complementary antitumor immunity induced by plasmid DNA encoding secreted and cytoplasmic human ErbB-2. J. Immunol.167,3367–3374 (2001).
  Medline CASGoogle Scholar
• 93  Pupa SM, Invernizzi AM, Forti S et al. Prevention of spontaneous neu-expressing mammary tumor development in mice transgenic for rat proto-neu by DNA vaccination. Gene Ther.8,75–79 (2001).
  Medline CASGoogle Scholar
• 94  Yip YL, Smith G, Koch J, Dubel S, Ward RL. Identification of epitope regions recognized by tumor inhibitory and stimulatory anti-ErbB-2 monoclonal antibodies: implications for vaccine design. J. Immunol.166,5271–5278 (2001).
  Medline CASGoogle Scholar
• 95  Riemer AB, Klinger M, Wagner S et al. Generation of peptide mimics of the epitope recognized by trastuzumab on the oncogenic protein Her-2/neu. J. Immunol.173,394–401 (2004).
  Medline CASGoogle Scholar
• 96  Jasinska J, Wagner S, Radauer C et al. Inhibition of tumor cell growth by antibodies induced after vaccination with peptides derived from the extracellular domain of Her-2/neu. Int. J. Cancer107,976–983 (2003).
  Medline CASGoogle Scholar
• 97  Riemer AB, Klinger M, Wagner S et al. Generation of peptide mimics of the epitope recognized by trastuzumab on the oncogenic protein Her-2/neu. J. Immunol.173,394–401 (2004).
  Medline CASGoogle Scholar
• 98  Riemer AB, Kraml G, Scheiner O, Zielinski CC, Jensen-Jarolim E. Matching of trastuzumab (Herceptin) epitope mimics onto the surface of Her-2/neu – a new method of epitope definition. Mol. Immunol.42,1121–1124 (2005).
  Medline CASGoogle Scholar
• 99  Atzori F, Tabernero J, Cervantes A et al. A Phase I pharmacokinetic and pharmacodynamic study of dalotuzumab (MK-0646), an anti-insulin-like growth factor-1 receptor monoclonal antibody, in patients with advanced solid tumors. Clin. Cancer Res.17,6304–6312 (2011).
  Medline CASGoogle Scholar
• 100  Wiedermann U, Wiltschke C, Jasinska J et al. A virosomal formulated Her-2/neu multi-peptide vaccine induces Her-2/neu-specific immune responses in patients with metastatic breast cancer: a Phase I study. Breast Cancer Res. Treat.119,673–683 (2010).
  Medline CASGoogle Scholar
• 101  Nagy JA, Dvorak AM, Dvorak HF. VEGF-A and the induction of pathological angiogenesis. Annu. Rev. Pathol.2,251–275 (2007).
  Medline CASGoogle Scholar
• 102  Folkman J. Anti-angiogenesis: new concept for therapy of solid tumors. Ann. Surg.175,409–416 (1972).
  Medline CASGoogle Scholar
• 103  Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat. Rev. Cancer3,401–410 (2003).
  Medline CASGoogle Scholar
• 104  Carpenito C, Davis PD, Dougherty ST, Dougherty GJ. Exploiting the differential production of angiogenic factors within the tumor microenvironment in the design of a novel vascular-targeted gene therapy-based approach to the treatment of cancer. Int. J. Radiat. Oncol. Biol. Phys.54,1473–1478 (2002).
  Medline CASGoogle Scholar
• 105  Casella I, Feccia T, Chelucci C et al. Autocrine-paracrine VEGF loops potentiate the maturation of megakaryocytic precursors through Flt1 receptor. Blood101,1316–1323 (2003).
  Medline CASGoogle Scholar
• 106  Monsky WL, Mouta Carreira C, Tsuzuki Y, Gohongi T, Fukumura D, Jain RK. Role of host microenvironment in angiogenesis and microvascular functions in human breast cancer xenografts: mammary fat pad versus cranial tumors. Clin. Cancer Res.8,1008–1013 (2002).
  Medline CASGoogle Scholar
• 107  Kim DW, Huamani J, Fu A, Hallahan DE. Molecular strategies targeting the host component of cancer to enhance tumor response to radiation therapy. Int. J. Radiat. Oncol. Biol. Phys.64,38–46 (2006).
  Medline CASGoogle Scholar
• 108  Perona R. Cell signalling: growth factors and tyrosine kinase receptors. Clin. Transl Oncol.8,77–82 (2006).
  Medline CASGoogle Scholar
• 109  Folkman J. Tumor suppression by p53 is mediated in part by the antiangiogenic activity of endostatin and tumstatin. Sci. STKE2006,PE35 (2006).
  MedlineGoogle Scholar
• 110  Naumov GN, Bender E, Zurakowski D et al. A model of human tumor dormancy: an angiogenic switch from the nonangiogenic phenotype. J. Natl Cancer Inst.98,316–325 (2006).
  MedlineGoogle Scholar
• 111  Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell86,353–364 (1996).
  Medline CASGoogle Scholar
• 112  Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn EA. Vascular endothelial growth factor and angiogenesis. Pharmacol. Rev.56,549–580 (2004).
  Medline CASGoogle Scholar
• 113  Ferrara N. Vascular endothelial growth factor as a target for anticancer therapy. Oncologist9(Suppl. 1),S2–S10 (2004).
  Medline CASGoogle Scholar
• 114  Saito H, Tsujitani S, Ikeguchi M, Maeta M, Kaibara N. Relationship between the expression of vascular endothelial growth factor and the density of dendritic cells in gastric adenocarcinoma tissue. Br. J. Cancer78,1573–1577 (1998).
  Medline CASGoogle Scholar
• 115  McMahon G. VEGF receptor signaling in tumor angiogenesis. Oncologist5(Suppl. 1),S3–S10 (2000).
  Medline CASGoogle Scholar
• 116  Ferrara N. The role of VEGF in the regulation of physiological and pathological angiogenesis. EXS (94),209–231 (2005).
  MedlineGoogle Scholar
• 117  Moldovan L, Moldovan NI. Role of monocytes and macrophages in angiogenesis. EXS (94),127–146 (2005).
  MedlineGoogle Scholar
• 118  Moldovan NI. Functional adaptation: the key to plasticity of cardiovascular “stem” cells? Stem Cells Dev.14,111–121 (2005).
  MedlineGoogle Scholar
• 119  Anghelina M, Krishnan P, Moldovan L, Moldovan NI. Monocytes/macrophages cooperate with progenitor cells during neovascularization and tissue repair: conversion of cell columns into fibrovascular bundles. Am. J. Pathol.168,529–541 (2006).
  Medline CASGoogle Scholar
• 120  Anghelina M, Krishnan P, Moldovan L, Moldovan NI. Monocytes and macrophages form branched cell columns in matrigel: implications for a role in neovascularization. Stem Cells Dev.13,665–676 (2004).
  Medline CASGoogle Scholar
• 121  Houck KA, Ferrara N, Winer J, Cachianes G, Li B, Leung DW. The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol. Endocrinol.5,1806–1814 (1991).
  Medline CASGoogle Scholar
• 122  Tischer E, Mitchell R, Hartman T et al. The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J. Biol. Chem.266,11947–11954 (1991).
  Medline CASGoogle Scholar
• 123  Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem. Biophys. Res. Commun.161,851–858 (1989).
  Medline CASGoogle Scholar
• 124  Fuh G, Wu P, Liang WC et al. Structure–function studies of two synthetic anti-vascular endothelial growth factor Fabs and comparison with the Avastin Fab. J. Biol. Chem.281,6625–6631 (2006).
  Medline CASGoogle Scholar
• 125  Dakappagari NK, Douglas DB, Triozzi PL, Stevens VC, Kaumaya PT. Prevention of mammary tumors with a chimeric HER-2 B-cell epitope peptide vaccine. Cancer Res.60,3782–3789 (2000).
  Medline CASGoogle Scholar
• 126  Vicari D, Foy KC, Liotta EM, Kaumaya PT. Engineered conformation-dependent VEGF peptide mimics are effective in inhibiting VEGF signaling pathways. J. Biol. Chem.286(15),13612–13625 (2011).
  Medline CASGoogle Scholar
• 127  Carmeliet P. Angiogenesis in life, disease and medicine. Nature438,932–936 (2005).
  Medline CASGoogle Scholar
• 128  Zhu Z, Witte L. Inhibition of tumor growth and metastasis by targeting tumor-associated angiogenesis with antagonists to the receptors of vascular endothelial growth factor. Invest. N. Drugs17,195–212 (1999).
  Medline CASGoogle Scholar
• 129  Oshima RG, Lesperance J, Munoz V et al. Angiogenic acceleration of Neu induced mammary tumor progression and metastasis. Cancer Res.64,169–179 (2004).
  Medline CASGoogle Scholar
• 130  Folkman J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med.285,1182–1186 (1971).
  Medline CASGoogle Scholar
• 131  Ferrara N. VEGF as a therapeutic target in cancer. Oncology69(Suppl. 3),S11–S16 (2005).
  Medline CASGoogle Scholar
• 132  Sereno M, Brunello A, Chiappori A et al. Cardiac toxicity: old and new issues in anti-cancer drugs. Clin. Transl Oncol.10,35–46 (2008).
  Medline CASGoogle Scholar
• 133  Nelson NJ. Angiogenesis research is on fast forward. J. Natl Cancer Inst.91,820–822 (1999).
  Medline CASGoogle Scholar
• 134  Smith WD, Wells PW, Burrells C, Dawson AM. Immunoglobulins, antibodies and inhibitors of parainfluenza 3 virus in respiratory secretions of sheep. Arch. Virol.49,329–337 (1975).
  Medline CASGoogle Scholar
• 135  Reinacher-Schick A, Pohl M, Schmiegel W. Drug insight: antiangiogenic therapies for gastrointestinal cancers – focus on monoclonal antibodies. Nat. Clin. Pract. Gastroenterol. Hepatol.5,250–267 (2008).
  Medline CASGoogle Scholar
• 136  Levitzki A. Tyrphostins – potential antiproliferative agents and novel molecular tools. Biochemical. Pharmacol.40,913–918 (1990).
  Medline CASGoogle Scholar
• 137  Khosravi Shahi P, Fernandez Pineda I. Tumoral angiogenesis: review of the literature. Cancer Invest.26,104–108 (2008).
  MedlineGoogle Scholar
• 138  Le Tourneau C, Raymond E, Faivre S. Sunitinib: a novel tyrosine kinase inhibitor. A brief review of its therapeutic potential in the treatment of renal carcinoma and gastrointestinal stromal tumors (GIST). Ther. Clin. Risk Manag.3,341–348 (2007).
  MedlineGoogle Scholar
• 139  Ryan AJ, Wedge SR. ZD6474 – a novel inhibitor of VEGFR and EGFR tyrosine kinase activity. Br. J. Cancer92(Suppl. 1),S6–S13 (2005).
  Medline CASGoogle Scholar
• 140  Bhojani N, Jeldres C, Patard JJ et al. Toxicities associated with the administration of sorafenib, sunitinib, and temsirolimus and their management in patients with metastatic renal cell carcinoma. Eur. Urol.53,917–930 (2008).
  Medline CASGoogle Scholar
• 141  Holash J, Davis S, Papadopoulos N et al. VEGF-trap: a VEGF blocker with potent antitumor effects. Proc. Natl Acad. Sci. USA99,11393–11398 (2002).
  Medline CASGoogle Scholar
• 142  Bianco F, Basini G, Grasselli F. Angiogenic activity of swine granulosa cells: effects of hypoxia and vascular endothelial growth factor Trap R1R2, a VEGF blocker. Domest. Anim. Endocrinol.28,308–319 (2005).
  Medline CASGoogle Scholar
• 143  Kaumaya PT, VanBuskirk AM, Goldberg E, Pierce SK. Design and immunological properties of topographic immunogenic determinants of a protein antigen (LDH-C4) as vaccines. J. Biol. Chem.267,6338–6346 (1992).
  Medline CASGoogle Scholar
• 144  Kaumaya PT, Berndt KD, Heidorn DB, Trewhella J, Kezdy FJ, Goldberg E. Synthesis and biophysical characterization of engineered topographic immunogenic determinants with alpha alpha topology. Biochemistry29,13–23 (1990).
  Medline CASGoogle Scholar
• 145  Kobs-Conrad S, Lee H, DiGeorge AM, Kaumaya PT. Engineered topographic determinants with alpha beta, beta alpha beta, and beta alpha beta alpha topologies show high affinity binding to native protein antigen (lactate dehydrogenase-C4). J. Biol. Chem.268,25285–25295 (1993).
  Medline CASGoogle Scholar
• 146  Srinivasan M, Wardrop RM, Gienapp IE, Stuckman SS, Whitacre CC, Kaumaya PT. A retro-inverso peptide mimic of CD28 encompassing the MYPPPY motif adopts a polyproline type II helix and inhibits encephalitogenic T cells in vitro. J. Immunol.167,578–585 (2001).
  Medline CASGoogle Scholar
• 147  Srinivasan M, Gienapp IE, Stuckman SS et al. Suppression of experimental autoimmune encephalomyelitis using peptide mimics of CD28. J. Immunol.169,2180–2188 (2002).
  Medline CASGoogle Scholar
• 148  Allen SD, Rawale SV, Whitacre CC, Kaumaya PT. Therapeutic peptidomimetic strategies for autoimmune diseases: costimulation blockade. J. Pept. Res.65,591–604 (2005).
  Medline CASGoogle Scholar
• 149  Kaumaya PT, Kobs-Conrad S, Seo YH et al. Peptide vaccines incorporating a ‘promiscuous’ T-cell epitope bypass certain haplotype restricted immune responses and provide broad spectrum immunogenicity. J. Mol. Recogn.6,81–94 (1993).
  Medline CASGoogle Scholar
• 150  Dakappagari NK, Pyles J, Parihar R, Carson WE, Young DC, Kaumaya PT. A chimeric multi-human epidermal growth factor receptor-2 B cell epitope peptide vaccine mediates superior antitumor responses. J. Immunol.170,4242–4253 (2003).
  Medline CASGoogle Scholar
• 151  Dakappagari NK, Lute KD, Rawale S et al. Conformational HER-2/neu B-cell epitope peptide vaccine designed to incorporate two native disulfide bonds enhances tumor cell binding and antitumor activities. J. Biol. Chem.280,54–63 (2005).
  Medline CASGoogle Scholar
• 152  Allen SD, Garrett JT, Rawale SV et al. Peptide vaccines of the HER-2/neu dimerization loop are effective in inhibiting mammary tumor growth in vivo. J. Immunol.179,472–482 (2007).
  Medline CASGoogle Scholar
• 153  Garrett JT, Rawale S, Allen SD et al. Novel engineered trastuzumab conformational epitopes demonstrate in vitro and in vivo antitumor properties against HER-2/neu. J. Immunol.178,7120–7131 (2007).
  Medline CASGoogle Scholar
• 154  Vicari D, Foy KC, Liotta EM, Kaumaya PT. Engineered conformation-dependent VEGF peptide mimics are effective in inhibiting VEGF signaling pathways. J. Biol. Chem.286,13612–13625 (2011).
  Medline CASGoogle Scholar
• 155  Foy KC, Liu Z, Phillips G, Miller M, Kaumaya PT. Combination treatment with HER-2 and VEGF peptide mimics induces potent anti-tumor and anti-angiogenic responses in vitro and in vivo. J. Biol. Chem.286,13626–13637 (2011).
  Medline CASGoogle Scholar
• 156  Kaumaya PT. Could precision-engineered peptide epitopes/vaccines be the key to a cancer cure? Future Oncol.7,807–810 (2011).
  Google Scholar
• 157  Lairmore MD, DiGeorge AM, Conrad SF, Trevino AV, Lal RB, Kaumaya PT. Human T-lymphotropic virus type 1 peptides in chimeric and multivalent constructs with promiscuous T-cell epitopes enhance immunogenicity and overcome genetic restriction. J. Virol.69,6077–6089 (1995).
  Medline CASGoogle Scholar
• 158  Partidos CD, Steward MW. Prediction and identification of a T cell epitope in the fusion protein of measles virus immunodominant in mice and humans. J. Gen. Virol.71(Pt 9),2099–2105 (1990).
  Medline CASGoogle Scholar
• 159  Paniana-Bordignon P, Tan A, Termijtelen A, Demotz S, Corradin G, Lanzavecchia A. Universally immunogenic T cell epitopes: promiscuous binding to human MHC class II and promiscuous recognition by T cells. Eur. J. Immunol.19,2237 (1989).
  MedlineGoogle Scholar
• 160  Cox E, Verdonck F, Vanrompay D, Goddeeris B. Adjuvants modulating mucosal immune responses or directing systemic responses towards the mucosa. Vet. Res.37,511–539 (2006).
  Medline CASGoogle Scholar
• 161  O’Hagan DT, Valiante NM. Recent advances in the discovery and delivery of vaccine adjuvants. Nat. Rev. Drug Discov.2,727–735 (2003).
  MedlineGoogle Scholar
• 162  McNeela EA, Mills KH. Manipulating the immune system: humoral versus cell-mediated immunity. Adv. Drug Deliv. Rev.51,43–54 (2001).
  Medline CASGoogle Scholar
• 163  Jackson DC, Lau YF, Le T et al. A totally synthetic vaccine of generic structure that targets Toll-like receptor 2 on dendritic cells and promotes antibody or cytotoxic T cell responses. Proc. Natl Acad. Sci. USA101,15440–15445 (2004).
  Medline CASGoogle Scholar
• 164  Daemen T, de Mare A, Bungener L, de Jonge J, Huckriede A, Wilschut J. Virosomes for antigen and DNA delivery. Adv. Drug Deliv. Rev.57,451–463 (2005).
  Medline CASGoogle Scholar
• 165  Diwan M, Tafaghodi M, Samuel J. Enhancement of immune responses by co-delivery of a CpG oligodeoxynucleotide and tetanus toxoid in biodegradable nanospheres. J. Control. Release85,247–262 (2002).
  Medline CASGoogle Scholar
• 166  Lynch JM, Briles DE, Metzger DW. Increased protection against pneumococcal disease by mucosal administration of conjugate vaccine plus interleukin-12. Infect. Immun.71,4780–4788 (2003).
  Medline CASGoogle Scholar
• 167  Kaumaya PTP, Kobs-Conrad S, DiGeorge AM, Stevens V. Denovo engineering of protein immunogenic and antigenic determinants. In: Peptides. Anantharamaiah GM (Ed.). Springer-Verlag, Berlin, Germany, 133–164 (1994).
  Google Scholar
• 168  Baselga J, Cortés J, Kim SB et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N. Engl. J. Med.366,109–119 (2012).
  Medline CASGoogle Scholar
• 169  Cho HS, Mason K, Ramyar KX et al. Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature421,756–760 (2003).▪▪ Elucidation of the structure of the HER-2 extracellular domain alone and in complex with the humanized monoclonal antibody trastuzumab.
  Medline CASGoogle Scholar
• 170  Garrett TP, McKern NM, Lou M et al. The crystal structure of a truncated ErbB2 ectodomain reveals an active conformation, poised to interact with other ErbB receptors. Mol. Cell11,495–505 (2003).
  Medline CASGoogle Scholar
• 171  Franklin MC, Carey KD, Vajdos FF, Leahy DJ, de Vos AM, Sliwkowski MX. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell5,317–328 (2004).▪▪ Provides significant insights into the structural interactions between the pertuzumab antibody and domain II of the HER-2 extracellular domain. Based on these interactions, it is possible to design specific B-cell epitopes that include the key amino acids that are important in binding.
  Medline CASGoogle Scholar
• 172  Kaumaya PT, Foy KC, Garrett J et al. Phase I active immunotherapy with combination of two chimeric, human epidermal growth factor receptor 2, B-cell epitopes fused to a promiscuous T-cell epitope in patients with metastatic and/or recurrent solid tumors. J. Clin. Oncol.27,5270–5277 (2009).
  Medline CASGoogle Scholar
• 173  Sundaram R, Dakappagari NK, Kaumaya PT. Synthetic peptides as cancer vaccines. Biopolymers66,200–216 (2002).
  Medline CASGoogle Scholar
• 174  Mizejewski GJ. Peptides as receptor ligand drugs and their relationship to G-coupled signal transduction. Expert Opin Invest. Drugs10,1063–1073 (2001).
  Medline CASGoogle Scholar
• 175  Hruby VJ. Conformational and topographical considerations in the design of biologically active peptides. Biopolymers33,1073–1082 (1993).
  Medline CASGoogle Scholar
• 176  Taylor EM, Otero DA, Banks WA, O’Brien JS. Retro-inverso prosaptide peptides retain bioactivity, are stable in vivo, and are blood-brain barrier permeable. J. Pharmacol. Exp. Ther.295,190–194 (2000).
  Medline CASGoogle Scholar
• 177  Fischer PM. The design, synthesis and application of stereochemical and directional peptide isomers: a critical review. Curr. Protein Peptide Sci.4,339–356 (2003).
  Medline CASGoogle Scholar
• 178  Fletcher MD, Campbell MM. Partially modified retro-inverso peptides: development, synthesis, and conformational behavior. Chem. Rev.98,763–796 (1998).
  Medline CASGoogle Scholar
• 179  Nagy JA, Benjamin L, Zeng H, Dvorak AM, Dvorak HF. Vascular permeability, vascular hyperpermeability and angiogenesis. Angiogenesis11,109–119 (2008).
  Medline CASGoogle Scholar
• 180  Gasparini G, Longo R, Toi M, Ferrara N. Angiogenic inhibitors: a new therapeutic strategy in oncology. Nat. Clin. Pract. Oncol.2,562–577 (2005).
  Medline CASGoogle Scholar
• 181  Keyt BA, Nguyen HV, Berleau LT et al. Identification of vascular endothelial growth factor determinants for binding KDR and FLT-1 receptors. Generation of receptor-selective VEGF variants by site-directed mutagenesis. J. Biol. Chem.271,5638–5646 (1996).
  Medline CASGoogle Scholar
• 182  Muller YA, Li B, Christinger HW, Wells JA, Cunningham BC, de Vos AM. Vascular endothelial growth factor: crystal structure and functional mapping of the kinase domain receptor binding site. Proc. Natl Acad. Sci. USA94,7192–7197 (1997).
  Medline CASGoogle Scholar
• 183  Muller YA, Chen Y, Christinger HW et al. VEGF and the Fab fragment of a humanized neutralizing antibody: crystal structure of the complex at 2.4 A resolution and mutational analysis of the interface. Structure6,1153–1167 (1998).▪▪ Maps the VEGF receptor binding site and also VEGF in complex with the Fab-binding antibody bevacizumab. The crystal structure of the complex was solved in this paper and also mutagenesis studies were performed to delineate which amino acids are important in binding.
  Medline CASGoogle Scholar
• 184  Zilberberg L, Shinkaruk S, Lequin O et al. Structure and inhibitory effects on angiogenesis and tumor development of a new vascular endothelial growth inhibitor. J. Biol. Chem.278,35564–35573 (2003).
  Medline CASGoogle Scholar
• 185  Muller YA, Christinger HW, Keyt BA, de Vos AM. The crystal structure of vascular endothelial growth factor (VEGF) refined to 1.93 A resolution: multiple copy flexibility and receptor binding. Structure5,1325–1338 (1997).
  Medline CASGoogle Scholar
• 186  Goodman M, Ro S, Yamazaki T et al. Topochemical design of bioactive peptides and peptidomimetics. Bioorg. Khim.18,1375–1393 (1992).
  Medline CASGoogle Scholar
• 187  Chorev M, Goodman M. Recent developments in retro peptides and proteins--an ongoing topochemical exploration. Trends Biotechnol.13,438–445 (1995).
  Medline CASGoogle Scholar
• 188  Chorev M. The partial retro-inverso modification: a road traveled together. Biopolymers80,67–84 (2005).
  Medline CASGoogle Scholar
• 189  Foy KC, Liu Z, Phillips G, Miller M, Kaumaya PT. Combination treatment with HER-2 and VEGF peptide mimics induces potent anti-tumor and anti-angiogenic responses in vitro and in vivo. J. Biol. Chem.286,13626–13637 (2011).
  Medline CASGoogle Scholar
• 190  Cardiff RD, Anver MR, Gusterson BA et al. The mammary pathology of genetically engineered mice: the consensus report and recommendations from the Annapolis meeting. Oncogene19,968–988 (2000).
  Medline CASGoogle Scholar
• 191  Hennighausen L. Mouse models for breast cancer. Oncogene19,966–967 (2000).
  Medline CASGoogle Scholar
• 192  Guy CT, Webster MA, Schaller M, Parsons TJ, Cardiff RD, Muller WJ. Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc. Natl Acad. Sci. USA89,10578–10582 (1992).
  Medline CASGoogle Scholar
• 193  Boggio K, Nicoletti G, Di Carlo E et al. Interleukin 12-mediated prevention of spontaneous mammary adenocarcinomas in two lines of Her-2/neu transgenic mice. J. Exp. Med.188,589–596 (1998).
  Medline CASGoogle Scholar
• 194  Gullick WJ, Bottomley AC, Lofts FJ et al. Three dimensional structure of the transmembrane region of the proto-oncogenic and oncogenic forms of the neu protein. EMBO J.11,43–48 (1992).
  Medline CASGoogle Scholar
• 195  Dankort D, Maslikowski B, Warner N et al. Grb2 and Shc adapter proteins play distinct roles in Neu (ErbB-2)-induced mammary tumorigenesis: implications for human breast cancer. Mol. Cell. Biol.21,1540–1551 (2001).
  Medline CASGoogle Scholar
• 196  Lin EY, Jones JG, Li P et al. Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases. Am. J. Pathol.163,2113–2126 (2003).
  MedlineGoogle Scholar
• 197  Zabuawala T, Taffany DA, Sharma SM et al. An ets2-driven transcriptional program in tumor-associated macrophages promotes tumor metastasis. Cancer Res.70,1323–1333 (2010).
  Medline CASGoogle Scholar
• 198  Pomerantz MM, Shrestha Y, Flavin RJ et al. Analysis of the 10q11 cancer risk locus implicates MSMB and NCOA4 in human prostate tumorigenesis. PLoS Genet.6,e1001204 (2010).
  MedlineGoogle Scholar
• 199  Yen L, You XL, Al Moustafa AE et al. Heregulin selectively upregulates vascular endothelial growth factor secretion in cancer cells and stimulates angiogenesis. Oncogene19,3460–3469 (2000).
  Medline CASGoogle Scholar
• 200  Izumi Y, Xu L, di Tomaso E, Fukumura D, Jain RK. Tumour biology: herceptin acts as an anti-angiogenic cocktail. Nature416,279–280 (2002).
  Medline CASGoogle Scholar
• 201  Konecny GE, Meng YG, Untch M et al. Association between HER-2/neu and vascular endothelial growth factor expression predicts clinical outcome in primary breast cancer patients. Clin. Cancer Res.10,1706–1716 (2004).
  Medline CASGoogle Scholar
• 202  Sun X, Kanwar JR, Leung E, Lehnert K, Wang D, Krissansen GW. Angiostatin enhances B7.1-mediated cancer immunotherapy independently of effects on vascular endothelial growth factor expression. Cancer Gene Ther.8,719–727 (2001).
  Medline CASGoogle Scholar
• 203  Kuo CJ, Farnebo F, Yu EY et al. Comparative evaluation of the antitumor activity of antiangiogenic proteins delivered by gene transfer. Proc. Natl Acad. Sci. USA98,4605–4610 (2001).
  Medline CASGoogle Scholar
• 204  Nair S, Boczkowski D, Moeller B, Dewhirst M, Vieweg J, Gilboa E. Synergy between tumor immunotherapy and antiangiogenic therapy. Blood102,964–971 (2003).
  Medline CASGoogle Scholar
• 205  Grunstein J, Roberts WG, Mathieu-Costello O, Hanahan D, Johnson RS. Tumor-derived expression of vascular endothelial growth factor is a critical factor in tumor expansion and vascular function. Cancer Res.59,1592–1598 (1999).
  Medline CASGoogle Scholar
• 206  Schneider BP, Wang M, Radovich M et al. Association of vascular endothelial growth factor and vascular endothelial growth factor receptor-2 genetic polymorphisms with outcome in a trial of paclitaxel compared with paclitaxel plus bevacizumab in advanced breast cancer: ECOG 2100. J. Clin. Oncol.26,4672–4678 (2008).
  Medline CASGoogle Scholar
• 207  Foy KC, Miller MJ, Moldovan N, Carson WE, Kaumaya PTP. 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. OncoImmunology doi:10.4161/onci.20708 (2012).
  Google Scholar
• 208  Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science307,58–62 (2005).▪▪ Discusses the benefits antiangiogenic agents have in the treatment of cancer. The article proposes the concept of tumor vasculature normalization, which results in better delivery of cancer therapeutics, thereby avoiding resistance and preventing tumor growth.
  Medline CASGoogle Scholar
• 209  Kerbel RS. Inhibition of tumor angiogenesis as a strategy to circumvent acquired resistance to anti-cancer therapeutic agents. Bioessays13,31–36 (1991).
  Medline CASGoogle Scholar
• 210  Foy KC, Miller MJ, Moldovan N, Bozanovic T, Carson WE, Kaumaya PTP. Immunotherapy with HER2 and VEGF peptide mimics plus metronomic paclitaxel causes superior antineoplastic effects in transplantable and transgenic mouse models of human breast cancer. OncoImmunology1(7), (2012) (In Press).
  Google Scholar
• 211  Nahta R. Pharmacological strategies to overcome HER2 cross-talk and trastuzumab resistance. Curr. Med. Chem.19,1065–1075 (2012).
  Medline CASGoogle Scholar
• 212  Roop RP, Ma CX. Endocrine resistance in breast cancer: molecular pathways and rational development of targeted therapies. Future Oncol.8,273–292 (2012).▪ Summarizes the development of resistance mechanisms in breast cancer with emphasis on the different molecular pathways and ideas on how future therapeutics should be developed.
  CASGoogle Scholar
• 213  Yakar S, Leroith D, Brodt P. The role of the growth hormone/insulin-like growth factor axis in tumor growth and progression: lessons from animal models. Cytokine Growth Factor Rev.16,407–420 (2005).
  Medline CASGoogle Scholar
• 214  Pollak MN, Schernhammer ES, Hankinson SE. Insulin-like growth factors and neoplasia. Nat. Rev. Cancer4,505–518 (2004).
  Medline CASGoogle Scholar
• 215  Pollak MN. Insulin-like growth factors and neoplasia. Novartis Found. Symp.262,84–98 Discussion 98–107, 265–268 (2004).
  Medline CASGoogle Scholar
• 216  Adams TE, Epa VC, Garrett TP, Ward CW. Structure and function of the type 1 insulin-like growth factor receptor. Cell. Mol. Life Sci.57,1050–1093 (2000).
  Medline CASGoogle Scholar
• 217  Yu H, Spitz MR, Mistry J, Gu J, Hong WK, Wu X. Plasma levels of insulin-like growth factor-I and lung cancer risk: a case–control analysis. J. Natl Cancer Inst.91,151–156 (1999).
  Medline CASGoogle Scholar
• 218  Hankinson SE, Willett WC, Colditz GA et al. Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet351,1393–1396 (1998).
  Medline CASGoogle Scholar
• 219  Bergmann U, Funatomi H, Yokoyama M, Beger HG, Korc M. Insulin-like growth factor I overexpression in human pancreatic cancer: evidence for autocrine and paracrine roles. Cancer Res.55,2007–2011 (1995).
  Medline CASGoogle Scholar
• 220  Ma J, Pollak MN, Giovannucci E et al. Prospective study of colorectal cancer risk in men and plasma levels of insulin-like growth factor (IGF)-I and IGF-binding protein-3. J. Natl Cancer Inst.91,620–625 (1999).
  Medline CASGoogle Scholar
• 221  Chan JM, Stampfer MJ, Giovannucci E et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science279,563–566 (1998).
  Medline CASGoogle Scholar
• 222  Wu X, Zhao H, Do KA et al. Serum levels of insulin growth factor (IGF-I) and IGF-binding protein predict risk of second primary tumors in patients with head and neck cancer. Clin. Cancer Res.10,3988–3995 (2004).
  Medline CASGoogle Scholar
• 223  Morgillo F, Woo JK, Kim ES, Hong WK, Lee HY. Heterodimerization of insulin-like growth factor receptor/epidermal growth factor receptor and induction of survivin expression counteract the antitumor action of erlotinib. Cancer Res.66,10100–10111 (2006).
  Medline CASGoogle Scholar
• 224  Kuribayashi A, Kataoka K, Kurabayashi T, Miura M. Evidence that basal activity, but not transactivation, of the epidermal growth factor receptor tyrosine kinase is required for insulin-like growth factor I-induced activation of extracellular signal-regulated kinase in oral carcinoma cells. Endocrinology145,4976–4984 (2004).
  Medline CASGoogle Scholar
• 225  Balana ME, Labriola L, Salatino M et al. Activation of ErbB-2 via a hierarchical interaction between ErbB-2 and type I insulin-like growth factor receptor in mammary tumor cells. Oncogene20,34–47 (2001).
  Medline CASGoogle Scholar
• 226  Camirand A, Lu Y, Pollak M. Co-targeting HER2/ErbB2 and insulin-like growth factor-1 receptors causes synergistic inhibition of growth in HER2-overexpressing breast cancer cells. Med. Sci. Monit.8,BR521–BR526 (2002).
  Medline CASGoogle Scholar
• 227  Nahta R, Yuan LX, Zhang B, Kobayashi R, Esteva FJ. Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. Cancer Res.65,11118–11128 (2005).
  Medline CASGoogle Scholar
• 228  Slomiany MG, Black LA, Kibbey MM, Day TA, Rosenzweig SA. IGF-1 induced vascular endothelial growth factor secretion in head and neck squamous cell carcinoma. Biochem. Biophys. Res. Commun.342,851–858 (2006).
  Medline CASGoogle Scholar
• 301  American Cancer Society. www.cancer.org
  Google Scholar
• 302  A Study to Evaluate Pertuzumab + Trastuzumab + Docetaxel vs. Placebo + Trastuzumab + Docetaxel in Previously Untreated Her2-Positive Metastatic Breast Cancer (CLEOPATRA). http://clinicaltrials.gov/ct2/show/NCT00567190?term=NCT00567190&rank=1
  Google Scholar
• 303  Vaccine Therapy in Treating Patients With Metastatic Solid Tumors. http://clinicaltrials.gov/ct2/show/NCT01376505?term=NCT+01376505&rank=1
  Google Scholar