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Review

Targeting epidermal growth factor receptor: novel therapeutics in the management of cancer

, &
Pages 367-380 | Published online: 10 Jan 2014

References

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  • •Specimens from 36 head and neck squamous cell carcinomas (HNSCC) were studied to identify a potential biomarker of the tumorigenesis process. Epidermal growth factor receptor (EGFR) expression remained elevated as tissue progressed from normal to hyperplasia to dysplasia, which may indicate that EGFR dysregulation might be a useful marker for identifying individuals at risk of tumor development.
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  • ••Focused on the association betweenoverexpression of EGFR and transforming growth factor (TGF)-a and the overall survival of patients with resectable small cell lung cancer. EGFR and TGF-a overexpression is frequent in early-stage non-small cell lung cancer (NCSLC) but is not associated with a survival difference, which makes EGFR more important in lung tumor formation than for tumor progression.
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  • •Determined the expression of TGF-a, arnphiregulin, CRIPTO, EGFR, ERbB-3 and tumor angiogenesis in a series of patients with Stage I—IIIA NSCLC treated with radical surgery The result suggested that evaluation of neoangiogenesis and amphiregulin overexpression = 0.02) are useful in addition to pathological staging to select high-risk NSCLC patients who may benefit from postsurgical systemic therapies.
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  • Turkeri LN, Erton ML, Cevik I et al. Impact of the expression of epidermal growth factor, transforming growth factor-CL and epidermal growth factor receptor on the prognosis of superficial bladder cancer. Urology51, 645–649 (1998).
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  • Ekstrand AJ, James CD, Cavanee WK et al Genes for epidermal growth factor receptor, transforming growth factor-CL and epidermal growth factor and their expression in human gliomas in vivo. Cancer Res 51, 2164–2172 (1991).
  • ••Demonstrated that EGFR gene amplification was detected in 50% of the studied samples of Grade 4 gliomas and only in one of 30 gliomas of lesser malignancy grade.
  • Solorzano C, Baker C, Tsan R et al Optimization for the blockade of epidermal growth factor receptor signaling for therapy of human pancreatic carcinoma. Clin. Cancer Res. 7, 2563–2572 (2001).
  • ••Confirmed the blockade of the EGFR signaling pathway by oral administration of EGFR tyrosine kinase inhibitor PKI-166 combined with intraperitoneal injection of gemcitabine for therapy of pancreatic carcinoma growing in pancreatic nude mice. PKI-166 inhibits the intracellular domain of EGFR tyrosine kinase with an IC50 value of 0.7 nrn.
  • Moyer JD, Barbacci EG, Iwata KK et al Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res. 57, 4838–4848 (1997).
  • •Demonstrated selective inhibition of EGFR tyrosine kinase by preventing autophosphorylation of EGFR in xenograft mice by administering CP-358,774. This inhibition also triggers apoptosis in DiFi human colon tumor cell in culture and blocks cell cycle in G1 phase.
  • Chu CT, Everiss KD, Wikstrand CJ et al Receptor dimerization is not a factor in the signaling activity of a transforming variant epidermal growth factor receptor (EGFRvIII). Biochem.j 324, 855–861 (1997).
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  • •Five specific monoclonal antibodies (mAbs) have identified the EGFRvIII on the cell surface of lung carcinomas and malignant glioma as determined by radioimmunoassay, ELISA, western blot, analytic flow cytometry, autophosphorylation and imrnunohistochemistry.
  • Chu CT, Everiss KD, Wikstrand CJ et al Receptor dimerization is not a factor in the signaling activity of a transforming variant epidermal growth factor (EGFRvIII). Biochem.j 324, 855–861 (1997).
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  • ••Indicated that therapy with antiEGFRmAb C225 has a significant antitumor effect by inhibiting angiogenesis, which was evaluated by immunohistochemistry and microvessel density
  • Huang SM, Bock JM, Harari PM. Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis and radiosensitivity in squamous cell carcinomas of the head and neck. Cancer Res. 59,1935-1940 (1999).
  • •Revealed that C225 enhances radiosensitivity and amplification of radiation-induced apoptosis in HNSCC.
  • Mandal M, Adam L, Mendelsohn J et al Nuclear targeting of BAXduring epidermal growth factor receptor-induced apoptosis in colorectal cancer cells. Oncogene 17, 999–1007 (1998).
  • Petit AM, Rak J, Hung MC et al Neutralizing antibodies against epidermal growth factor and ERB-2/neu receptor tyrosine kinases downregulate vascular endothelial growth factor production by tumor cells in vitm and in viva angiogenic implications for signal transduction therapy of solid tumors. Am J. Farhat. 151, 1523–1530 (1997).
  • Bruns CJ, Harbison MT, Davis DW et al. Epidermal growth factor receptor blockade with C225 plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by anti-angiogenic mechanisms. Clin. Cancer Res. 6,1936-1948 (2000).
  • Naramura M, Gillies SD, Mendelsohn J et al Therapeutic potential of chimeric and murine anti-epidermal growth factor receptor antibodies in a metastasis model for human melanoma. Cancer Immunol Immunother. 37,343–349 (1993).
  • Mendelsohn J. Blockade of receptors for growth factors: an anticancer therapy - the fourth annual Joseph H Burchenal American association for Cancer Research, clinical research award lecture. Clin. Cancer Res. 6,747–753 (2000).
  • Fan Z, Masui H, Atlas I et al Blockade of epidermal growth factor receptor function by bivalent and monovalent fragments of 225 anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res. 53, 4322–4328 (1993).
  • ••Explored the mechanism by whichantiEGFR 225 mAb inhibits cell proliferation by comparing the activity of native 225 mAb with the response to bivalent 225Fab2 and monovalent 225Fab fragments.
  • Baselga J, Norton L, Masui H et al Antitumor effects of doxorubicin in combination with anti-epidermal growth factor receptor monoclonal antibodies. J. Natl Cancer Inst. 85,1327–1333 (1993).
  • Fan Z, Baselga J, Masui H et al Antitumor effect of anti-epidermal growth factor receptor monoclonal antibodies plus cis-diamminedichloroplatinum on well established A431 cell xenografts. Cancer Res. 53,4637–4642 (1993).
  • Ciardiello F, Bianco R, Damiano V et al Antitumor activity of sequential treatment with topotecan and anti-epidermal growth factor receptor monoclonal antibody C225. Clin. Cancer Res. 5,909-916 (1999).
  • •Evaluated the combination of mAb C225 with topotecan in human ovarian, breast and colon cancer cell lines, which expressed functional EGFR This combination markedly enhanced apoptotic cell death and provided the rationale of this combination of anticancer therapy in clinical trial.
  • Baselga J, Pfister D, Cooper MR et al Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin. Clin. Oiled 18,904–914 (2000).
  • Gunnett K, Motzer R, Amato R et al Phase II study of anti-epidermal growth factor receptor (EGFR) antibody C225 alone in patients with metastatic renal cell carcinoma. Proc. Am. Soc. Clin. Oncol 389 (1999) (Abstract 19).
  • Huag SM, Harari PM. Modulation of radiation response after epidermal growth factor receptor blockade in squamous cell carcinomas: inhibition of damage repair, cell cycle kinetics and tumor angiogenesis. Clin. Cancer Res. 6,2166–2174 (2000).
  • •Suggests that the profound in vivo antitumor activity identified in the xenograft setting when C225 is combined with radiation derives from more than simply the antiproliferative and cell cycle affects of EGFR system inhibition. In addition to antiproliferative growth inhibition, EGFR blockade with C225 appears to influence the capacity of human squamous cell carcinoma to effect DNA repair after exposure to radiation and to express classic markers of tumor angiogenesis.
  • Ezekiel MP, Bonner JA, Robert E Phase I trial of chimerized epidermal growth factor receptor (EGFR) antibody in combination with once-daily or twice-daily irradiation for locally advanced head and neck malignancies. Proc. Am. Soc. Clin. Oncol (1999) (Abstract 1501).
  • Baselga J. Monoclonal antibodies directed at growth factor receptors. Ann. Oncol 11 (Suppl. 13), 187–190 (2000).
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  • ••Demonstrated that no significant sideeffects were observed using escalating doses of monoclonal antibody RG-83852 by intravenous infusion in patients with NSCLC or head and neck cancer. High degree of EGFR saturation (>50%) was observed at doses greater than 200 mg/m2 and EGFR saturation was estimated to be 100% at dose level of 600 mg/m2.
  • Baselga J, Pfister D, Cooper MR et al Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin. Clin. Oncol 18,904–914 (2000).
  • •Evaluated the pharrnacokinetics and toxicity of C225 in patients with advanced tumor overexpression of EGFR C225 has dose-dependant pharmacokinetics and doses that achieve saturation of systemic clearance are well tolerated. C225 given in combination with cisplatin has biologic activity at pharmacologically relevant doses. C225-associated toxicity was also minimal.
  • Crombet-Ramos T, Torres L, Salano M. Pharmacological and clinical evaluation of the humanized antiEGFR monoclonal antibody h-R3 in patients with advanced epithelial carcinomas. Proc. Am. Soc. Clin. Oncol (2001) (Abstract 1012).
  • Yang XD, Jia XC, Corvalan J et al. Eradication of established tumors by a fully human monoclonal antibody to the epidermal growth factor receptor without concomitant chemotherapy. Cancer Res. 59, 1236–1243 (1999).
  • ••Revealed the ability of a fully humanmonoclonal antibody to completely eradicate A431 xenografts in treated mice for more than 8 months.
  • Figlin RA, Belldegrun A, Lohner ME. ABX-EGF: a fully humanized antiEGF receptor antibody in patients with advanced cancer. Proc. Arn. Soc. Clin. Oncol (2001) (Abstract 1102).
  • Modjtahedi H, Hickish T, Nicolson M et al. Phase I trial and tumor localization of the antiEGFR monoclonal antibody ICR62 in head and neck or lung cancer. BE Cancer73, 228–235 (1996).
  • Hoffman T, Hafner D, Ballo H et al Antitumor activity of antiepidermal growth factor receptor monoclonal antibodies and cisplatin in ten human head and neck squamous cell carcinoma lines. Anticancer Res. 17,4419–4426 (1997).
  • Stragliotto G, Vega F, Stasiecki P et al Multiple infusions of antiepidermal growth factor receptor (EGFR) monoclonal antibody (EMD 55900) in patients with recurrent malignant gliomas. Eur. I Cancer 32A, 636–640 (1996).
  • Sartor C. Biological modifiers as potential radiosensitizers: targeting the epidermal growth factor receptor family. Semin. Oncol (In Press).
  • Mendelsohn J, Fan Z. Epidermal growth factor receptor family and chemosensitization. I Natl Cancer Inst. 89, 341–343 (1997).
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  • Akiyama T, Saito T, Ogawara H et al Tumor promoter and epidermal growth factor stimulate phosphorylation of the c-ErbB-2 gene product in MKN-7 human adenocarcinoma cells. Mal Cell Biol. 8, 1019–1926 (1988).
  • Fava R, Cohen S. Isolation of a calcium- dependent 35-kDa substrate for the epidermal growth factor receptor/kinase from A-431 cells. Bid Chem. 259, 2636–2645 (1984). loo Haigler HT, Schlaepfer DD, Burgess WH. Characterization of lipocortin I and an immunologically unrelated 33-kDa protein as epidermal growth factor receptor/kinase substrate and phospholipase A2 inhibitors. I Rio. Chem. 262,6921-6930 (1987).
  • Fry DW, Kraker AJ, McMichael A et al A specific inhibitor of the epidermal growth factor receptor tyrosine kinase. Science 265, 1093–1095 (1994).
  • Karnes WE, Weller SG, Adjei PN et al Inhibition of epidermal growth factor receptor kinase induces protease-dependent apoptosis in human colon cancer cells. Gastroenterology114, 930–939 (1998).
  • He Y, Zeng Q, Drenning SD et al Inhibition of human squamous cell carcinoma growth in vivo by epidermal growth factor receptor antisense RNA transcribed from the U6 promoter. I Natl Cancer Inst. 90,1080–1087 (1998).
  • Fry DW. Inhibition of the epidermal growth factor receptor family of tyrosine kinases as an approach to cancer chemotherapy: progression from reversible to irreversible inhibitors. Phatmacol Ther 82,207–218 (1999).
  • Zaman GJ, Vink PM, Van den Doelen AA et al Tyrosine kinase activity of purified recombinant cytoplasmic domain of platelet-derived growth factor 0-receptor (0-PDGFR) and discovery of a novel inhibition of receptor tyrosine kinases. Biochem. Pharmacol 57,57–64 (1999)
  • Smaill JB, Palmer BD, Rewcastle GW et al Tyrosine kinase inhibitors: 15,4-(Phenylamino)quinazoline and 4-(phenylamino)pyrido[d]pyrimidine acrylamides as irreversible inhibition of the ATP binding site of the epidermal growth factor receptor. I Merl Chem. 42, 1803–1815 (1999).
  • Showalter HD, Bridger AJ, Zhou H et al Tyrosine kinase inhibitors 16,6,5,6-tricyclic benzothieno3,2-dpyrimidines and pyrimido5,4-b- and -4,5- bindoles as potent inhibitions of epidermal growth factor receptor tyrosine kinase. j Merl Chem. 42, 5464–5474 (1999).
  • Noonberg SB, Benz CC. Tyrosine kinase inhibitors targeted to the epidermal growth factor receptor subfamily: role as anticancer agents. Drugs 59, 753–767 (2000).
  • Ghosh S, Zheng Y, Jun X et al a-cyano-3-hydroxy-3-methy-N14-(trifluoromethoxy)phenyl] propenamide: an inhibitor of the epidermal growth factor receptor tyrosine kinase with potent cytotoxic activity against breast cancer cells. Clin. Cancer Res. 4, 2657–2668 (1998).
  • Sudbeck EA, Liu XP, Narla RK et al. Structure-based design of specific inhibitors of Janus kinase 3 as apoptosis-inducing antileukemic agents. Clin. Cancer Res. 5, 1569–1582 (1999).
  • ••Explored several structural-based designs ofdimethoxyquinazoline compounds which caused potent and specific inhibitory activity against JAK3-expressing human leukemia cell lines. These specific inhibitors provided the basis for the design of new treatment strategies against acute lymphoblastic leukemia. in Lane HA, Beuvink I, Motoyama AB et al. ERB-B2 potentiates breast tumor proliferation through modulation of p27 (KIP1)-CDK2 complex formation: receptor overexpression does not determine growth dependency. Mal Cell Biol. 20, 3210–3223 (2000).
  • Woodburn JR, Barker AJ, Gibson KH et al ZD-1839, an epidermal growth factor tyrosine kinase inhibitor selected for clinical development. Pmc. Am. Assoc. Cancer Res. (1997) (Abstract 4251).
  • Sirotnak F, Zakowski M, Liller V et al Efficacy of cytotoxic agents against human tumor xenografts is markedly enhanced by coadministration of ZD1839 (IRESSA), an inhibitor of EGFR tyrosine kinase. Clin. Cancer Res. 6, 4885–4892 (2000).
  • Woodburn JR, Kendrew J, Fennell M et al ZD-1839 (IRESSA), a selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI): inhibition of c-FOS mRNA, an intermediate marker of EGFR activation, correlates with tumor growth inhibition. Proc. Am Assoc. Cancer Res. (2000) (Abstract 2552).
  • Cardiello F, Caputo R, Bianco R et al. Antitumor effect and potentiation of cytotoxic drugs activity in human cancer cells by ZD-1839 (IRESSA), an epidermal growth factor receptor-selective tyrosine kinase inhibitor. Clin. Cancer Res. 6, 2053–2063 (2000).
  • •The antiproliferative activity of gefinitib alone or in combination with cytotoxic drugs was evaluated in human ovarian, breast and colon cancer cells that coexpress EGFR and TGF-a. A dose-dependent supra-additive increase in growth inhibition was observed when cancer cells were treated with each cytotoxic drug and gefinitib, demonstrating the antitumor effect of this EGFR-selective tyrosine kinase inhibitor.
  • Ciardiello F, Damiano V, Bianco R et al Inhibition of EGFR-tyrosine kinase by ZD1839 (IRESSA) leads to antiproliferative and anti-angiogenic effects in human GEO colon cancer xenografts in combination with paclitaxel. Proc. Am. Assoc. Cancer Res. (2001) (Abstract 4580).
  • Normanno N, Campiglio M, De Luca A et al Co-operative inhibitory effect of ZD1839 (IRESSA) in combination with trastuzumab on human breast cancer cell growth. Proc. Am. Assoc. Cancer Res. (2001) (Abstract 4156).
  • Baselga J, Herbst R, LoRusso P et al Continuous administration of ZD-1839 (IRESSA), a novel oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected tumor types: evidence of activity and good tolerability. Proc. Am Sx. Clin. Oncol. (2000) (Abstract 686).
  • Negoro S, Nakagawa K, Fukuoka M et al Final results of a Phase I intermittent dose-escalation trial of ZD 1839 (IRESSA®) in Japanese patients with various solid tumors. Proc. Am Soc. Clin. Oncol (2001) (Abstract 1292).
  • Noonberg S, Benz C. Tyrosine kinase inhibitors targeted to the epidermal growth factor receptor subfamily. Drugs 59, 753–767 (2000).
  • Bianco R, Yakes FM, Mills GB et al. EGF receptor-overexpressing tumor cells that lack PTEN/MMAC1 and RB are resistant to small molecule EGFR kinase inhibitors. Proc. Am Assoc. Cancer Res. (2001) (Abstract 4567).
  • Pollack V, Savage D, Baker D et al. Inhibition of epidermal growth factor receptor-associated tyrosine phosphorylation in human carcinomas with CP-358,774: dynamics of receptor inhibition in situ and antitumor effects in athymic mice. JPET291, 739–748 (1999).
  • Iwata K, Miller PE, Barbacci EG et al CP-358,774: a selective EGFR tyrosine kinase inhibitor with potent antiproliferative activity against head and neck tumor cells. Proc. Am. Assoc. Cancer Res. (1997) (Abstract 4248).
  • Senzer NN, Soulieres D, Siu L et al Phase II evaluation of OSI-774, a potent oral antagonist of the EGFR-TK in patients with advanced squamous cell carcinoma of the head and neck. Pmc. Am. Soc. Clin. Oncol (2001) (Abstract 6).
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