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A new approach to cancer therapy was first proposed in 1981 by John Mendelsohn, M.D., and Gordon Sato, Ph.D. They hypothesized that inhibition of critical growth promoting signals from the tyrosine protein kinase of EGF receptors might prevent cancer cell proliferation. Twenty-four years later, this approach to cancer treatment has moved into clinical practice and dozens of agents that block growth factor receptors and tyrosine kinases are in clinical trials.

By 1980 it had been discovered that cell growth and division could be triggered through activation of EGF receptors on the cell surface by growth factors, EGF and TGFa, which the tumor cells could produce in an autocrine fashion, and that the growth signal resulted from ligand-induced activation of a newly described tyrosine kinase contained in the intracellular portion of the receptor. Data were also accumulating that EGF receptors were expressed in high numbers in a variety of epithelial cancers. The research on EGF receptors carried out by Mendelsohn and numerous collaborators during the ensuing 15 years provided the original demonstration that both inhibition of a growth factor receptor and inhibition of a tyrosine kinase could be fruitful approaches to creating new categories of anticancer agents (reviewed, 29-31). 

Mendelsohn’s laboratory discovered the mechanism by which blockade of EGF receptors inhibits cell proliferation. Progression of cells through the cycle of DNA synthesis and cell division requires sequential activation of a series of cyclin-dependent kinases. EGF receptor blockade by monoclonal antibody 225 results in the production of an inhibitor, p27Kip1, which inactivates these kinases, thereby preventing phosphorylation of Rb and inhibiting cells from entry into S phase17-19. A similar mechanism of action was subsequently reported by others for Herceptin, and for the low molecular weight, soluble inhibitors of EGF receptors. Other mechanistic studies documented the effects of monoclonal antibody binding upon EGF receptors5,8,10,13, and demonstrated that C225 is capable of mediating antibody-dependent cellular cytoxicity12.

Collaborators with Mendelsohn and other investigators have discovered additional mechanisms which may be critical to the antitumor activity of monoclonal antibody 225. In response to blockade of EGF receptors, human tumor cells were found to produce markedly reduced levels of factors promoting angiogenesis, and new blood vessel formation in human tumor xenografts was inhibited26. In addition, EGF receptor blockade was found to activate pro-apoptotic molecules and deactivate molecules that prevent apoptosis14,20,25.

In fact all six of the acquired characteristics of cancer cells, described by Hanahan and Weinberg in their 1990 paper in Cell, are inhibited when EGF receptor tyrosine kinase is inhibited. Further research with collaborators identified two additional possible mechanisms of action for antibody 225: mediation of antibody dependent cellular cytotoxicity (ADCC)12 and inhibition of DNA repair after radiation or chemotherapy.

A critical observation came from the laboratory of Michael Sela, Ph.D., who found that blockade of EGF receptors combined with concurrent chemotherapy with cisplatin produced augmented antitumor activity in animal xenograft models. Mendelsohn and his collaborators followed up these observations with detailed studies of monoclonal antibody 225 administered in combination with three different chemotherapeutic agents, doxorubicin, cisplatin, or paclitaxel9,11. Whereas maximal therapy with either anti-EGF receptor antibody alone or chemotherapy alone could not produce complete regression of well-established human tumors growing in nude mice, combination therapy with antibody plus drug completely eradicated large tumors. Collaborators and others have demonstrated synergistic action of 225 plus radiotherapy against tumor xenografts23. These preclinical studies and others performed by Mendelsohn’s laboratory supported the design of a large number of clinical trials with these antibodies in combination with chemotherapy or radiotherapy.

The murine anti-EGF receptor monoclonal antibody 225 was introduced into clinical trials in the late 1980s. While Mendelsohn has never treated a patient with 225, he participated actively in designing this and subsequent trials for over a decade. This Phase I trial was the first in humans to use an agent blocking the EGF receptor and an agent inhibiting a tyrosine kinase. The results were critical for the future development of therapies targeting receptors and tyrosine kinases. First and foremost, the trial established the safety of this approach to treatment. It was shown that tracer-labeled 225 accumulated selectively in primary and metastatic sites of lung cancer (known to express high levels of EGF receptors)7. Pharmacokinetics were favorable, with receptor-saturating levels of antibody maintained in the blood for a period of days. Notably, all patients developed antibodies against the murine monoclonal antibody. On the basis of this successful trial, the National Cancer Institute contracted with a company to use recombinant DNA technology to produce a human : murine chimeric version of 225.

Subsequently, Herceptin entered the clinic. In 1995 Baselga, Mendelsohn, Norton and collaborators reported a Phase II clinical trial showing for the first time that Herceptin treatment produced objective clinical responses in 10% of patients with advanced breast cancer16. This was the first proof-of-concept in the clinic that antireceptor antibodies can be active anticancer agents in patients. Mendelsohn and colleagues also showed augmentation of antitumor activity for Herceptin plus doxorubicin or paclitaxel against breast cancer xenografts21. These drug combinations were used in the randomized registration trial of Herceptin plus or minus chemotherapy for breast cancer, that led to FDA approval.

The human : murine chimeric monoclonal antibody derived from 225 is called C22515. ImClone Systems Inc. licensed C225 from the University of California in 1993 and began clinical trials in 1996. Once safety and pharmacokinetics of human : murine chimeric C225 were established clinical studies with combination therapy were initiated, based on the preclinical observations of Mendelsohn and collaborators (reviewed, 29-31). Phase I and II clinical trials with C225 plus chemotherapy or radiotherapy against a number of types of cancer showed safety, as well as efficacy in some patients24.

Phase II trials, reported at the American Society of Clinical Oncology (ASCO) Annual Meeting in 2001, showed a response rate of 22.5% when patients with colon cancer progressing while on irinotecan therapy were treated with irinotecan plus C225, and a response rate of 23% when patients with head and neck cancer progressing while on cisplatin therapy were treated with cisplatin plus C22528. In addition, patients with advanced pancreatic cancer treated with gemcitabine plus C225 had a response rate of 12.5% with a one year survival of 32.5%, compared with the pivotal trial of gemcitabine alone which gave an 18% one year survival rate. These observations have been followed up by additional trials sponsored by ImClone in partnership with Bristol-Myers Squibb. To date, many thousands of patients have been treated with C225 (reviewed, 29-31 ). 

On the basis of the 22.5% response rate to C225 plus irinotecan in patients whose colon cancers were no longer responding to irinotecan, ImClone sought accelerated regulatory approval for this indication in 1991. The FDA did not agree, and requested a randomized trial, including comparable patients treated with C225 alone.

The results of ImClone’s Phase II trial of C225 alone in patients with colorectal cancer progressing while on irinotecan therapy were reported at ASCO in 2002, showing a response rate of 10.5%. The randomized Phase III trial requested by the FDA was carried out in Europe on patients who initially responded and subsequently demonstrated disease progression on irinotecan therapy. The results were reported at the ASCO meeting in 2003. When irinotecan treatment was continued and C225 was added, the objective response rate was 22.9%. When the irinotecan was discontinued and C225 treatment was given alone the response rate was 10.8%. While both groups demonstrated the efficacy of C225, the advantage of combination therapy was highly statistically significant. This study confirmed the hypothesis, derived from Mendelsohn’s preclinical data, that blockade of EGF receptor activity with monoclonal antibody C225 could reverse resistance to chemotherapy.

On the basis of these results, the FDA approved C225 (cetuximab/Erbitux) for advanced, irinotecan-refractory colorectal cancer, on February 12, 2004.

Data from a Phase II trial of radiation therapy in combination with C225 showed a striking 100% response rate (12 complete and 2 partial responses) in patients with advanced head and neck cancer, and the results of a Phase III randomized trial, reported in 2004, showed a nearly 50% extension of median survival, from 28 to 54 months, when C225 was added to standard radiation treatment, compared to treatment with radiation alone. In 2006 the FDA approved use of C225 with radiation for primary therapy of head and neck cancer and C225 alone for recurrent disease. The Phase III EXTREME trial reported at ASCO 2007 showed a 37% increase in survival time when C225 was added to cytotoxic chemotherapy as primary treatment for recurrent or metastatic head and neck cancer.

Recent clinical trials with low molecular weight, soluble inhibitors of receptor tyrosine kinases, with varying specificity for the EGF receptor, have also shown promise. The most advanced of these are gefitinib and erlotinib. Gefitinib was approved by the FDA in 2003 as monotherapy treatment of refractory non-small cell lung cancer, based on a response rate of 11%. However a subsequent Phase III trial failed to demonstrate prolongation of life and the FDA has restricted the use of gefitinib in lung cancer to patients who had responded. Subsequently, erlotinib treatment of non-small cell lung cancer demonstrated prolongation of life and received regulatory approval for this form of cancer. Earlier, in 1999, treatment with monoclonal antibody Herceptin against HER-2 was approved by the FDA for HER-2 positive breast cancer.

Today there are over a dozen inhibitors of receptors in the EGF receptor family that are being investigated in clinical trials, worldwide33. And drugs against many other tyrosine kinases are demonstrating activity in patients. Thus, the original hypothesis that inhibiting receptors for growth factors and inhibiting tyrosine kinase signaling activity might be a new form of anticancer therapy has been validated, and is making a substantial impact on cancer treatment. A spectacular recent success is Gleevec against the bcr/abl tyrosine kinase for treatment of chronic myelogenous leukemia.

A major challenge is identifying the patients who will respond to EGF receptor blockade, since in the trials that have been reported with both monoclonal antibodies and low molecular weight inhibitors of EGF receptor tyrosine kinase only a minority of patients with advanced cancer have responded. Studies exploring molecular markers are emphasizing pharmacodynamics27, proteomics, expression arrays and mutational analysis of DNA and assessment of gene copy number to attempt to predict which patients are likely to respond to these agents. Clinical trials are underway in patients with early stages of a variety of types of cancer are exploring both monoclonal antibodies and low molecular weight anti-EGF receptor tyrosine kinase inhibitors, both alone and in combination with other new targeted therapies22. In December 2007 there were more than 200 active trials with C225, involving 30,000 patients.

In summary, the field of EGF receptor tyrosine kinase inhibition has become a major area of research and clinical care in oncology today, involving many dozens of clinical studies and a number of approved anti-cancer agents, as a result of the pioneering research initiated by Mendelsohn and his colleagues over 20 years ago and pursued by Mendelsohn for two decades in the laboratory and in the clinic.

Mendelsohn's Contributions Include:

First hypothesis, with Gordon Sato, Ph.D., that inhibition of EGF receptors and of a tyrosine kinase might be an effective anticancer treatment. 1980

First creation of an anti-EGF receptor/anti-tyrosine kinase agent that blocked receptor kinase activation and inhibited cell growth. 1983-84

First clinical trial with an agent targeting a growth factor receptor and a tyrosine kinase. Demonstrated safety and feasibility. 1990

First clinical trial with a monoclonal antibody designed to alter a biological function, not to elicit an immune response.  1990

First studies demonstrating mechanisms by which inhibition of EGF receptor tyrosine kinase inhibits cell proliferation and other cellular functions. 1996

First clinical trial providing proof of concept that an antireceptor agent (Herceptin) used alone could produce a clinically useful response rate (10%) in patients. 1996

First clinical trial demonstrating that addition of an EGF receptor inhibitor could overcome resistance to a chemotherapeutic agent (cisplatin in head and neck cancer). 2001

Selected References (by date of publication)

  1. Kawamoto T, Sato JD, Le A, Polikoff J, Sato GH, Mendelsohn J. Growth stimulation of A431 cells by EGF: Identification of high affinity receptors for epidermal growth factor by an anti-receptor monoclonal antibody. Proc Natl Acad Sci USA 80:1337-1341, 1983.
  2. Sato JD, Kawamoto T, Le AD, Mendelsohn J, Polikoff J, Sato GH. Biological effects in vitro of monoclonal antibodies to human EGF receptors. Mol Biol Med 1:511-529, 1983.
  3. Gill GN, Kawamoto T, Cochet C, Le A, Sato JD, Masui H, McLeod C, Mendelsohn J. Monoclonal anti-epidermal growth factor receptor antibodies which are inhibitors of epidermal growth factor binding and antagonists of epidermal growth factor-stimulated tyrosine protein kinase activity. J Biol Chem 259:7755-7760, 1984.
  4. Masui H, Kawamoto T, Sato JD, Wolf B, Sato GH, Mendelsohn J. Growth inhibition of human tumor cells in athymic mice by anti-EGF receptor monoclonal antibodies. Cancer Res 44:1002-1007, 1984.
  5. Mendelsohn J, Masui H, Goldenberg A. Anti-epidermal growth factor receptor monoclonal antibodies may inhibit A431 tumor cell proliferation by blocking on autocrine pathway. Trans Assoc Am Physicians C:173-178, 1987.
  6. Goldenberg A, Masui H, Divgi C, Kamrath H, Pentlow K, Mendelsohn J. EGF receptor overexpression and localization of nude mouse xenografts using 111Indium labeled anti-EGF receptor monoclonal antibody. J Natl Cancer Inst 81:1616-1625, 1989.
  7. Divgi,C.R.; Welt,S.; Kris,M.; Real,F.X.; Yeh,S.D.J.; Gralla,R.; Merchant,B.; Schweighart,S.; Unger,M.; Larson,S.M.; Mendelsohn,J. Phase I and imaging trial of indium 111-labeled anti-epidermal growth factor receptor monoclonal antibody 225 in patients with squamous cell lung carcinoma. J Natl Cancer Inst 83:97-104, 1991.
  8. Van de Vijver M, Kumar R, Mendelsohn J. Ligand-induced activation of A431 cell EGF receptors occurs primarily by an autocrine pathway that acts upon receptors on the surface rather than intracellularly. J Biol Chem 266:7503-7508, 1991.
  9. Baselga J, Norton L, Masui H, Pandiella A, Coplan K, Miller WH, Mendelsohn J. Anti-tumor effects of doxorubicin in combination with anti-epidermal growth factor receptor monoclonal antibodies. J Natl Cancer Inst 85 (16): 1327-1333, 1993.
  10. Fan Z, Masui H, Atlas I, Mendelsohn J. Blockade of epidermal growth factor (EGF) receptor function by bivalent and monovalent fragments of 225 anti-EGF receptor monoclonal antibody. Cancer Res 53:4322-4328, 1993.
  11. Fan Z, Baselga J, Masui H, Mendelsohn J. Antitumor effect of anti-EGF receptor monoclonal antibodies plus cis-Diamminedichloroplatinum on well established A431 cell xenografts. Cancer Res 53:4637-4642, 1993.
  12. Naramura M, Gillies SD, Mendelsohn J, Reisfeld RA, Mueller BM. 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.
  13. Fan Z, Lu Y, Wu X, Mendelsohn J. Antibody-induced epidermal growth factor receptor dimerization mediates inhibition of autocrine proliferation of A431 squamous carcinoma cells. J Biol Chem 269:27595-27602, 1994.
  14. Wu X, Fan Z, Masui H, Rosen N, Mendelsohn J. Apoptosis induced by an anti-epidermal growth factor receptor monoclonal antibody in a human colorectal carcinoma cell line and its delay by insulin. J Clin Invest 95:1897-1905, 1995.
  15. Goldstein NI, Prewett M, Zuklys K, Rockwell P, Mendelsohn J. Biological efficacy of a chimeric antibody to the epidermal growth factor receptor in a human tumor xenograft model. Clin Cancer Res 1:1311-1318, 1995.
  16. Baselga J, Tripathy D, Mendelsohn J, Baughman S, Benz CC, Dantis L, Sklarin NT, Seidman AD, Hudis CA, Moore J, Rosen PP, Twaddeell T, Henderson IC, Norton L. Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol 14:737-744, 1996.
  17. Wu X, Rubin M, Fan Z, DeBlasio T, Soos T, Koff A, Mendelsohn J. Involvement of p27KIP1 in G1 arrest mediated by an anti-epidermal growth factor receptor monoclonal antibody. Oncogene 12:1397-1403, 1996.
  18. Peng D, Fan Z, Lu Y, DeBlasio T, Scher H, Mendelsohn J. Anti-epidermal growth factor receptor monoclonal antibody 225 upregulates p27Kip1 and induces G1 arrest in prostatic cancer cell line DU145. [Advances in Brief] Cancer Res 56:3666-3669, 1996.
  19. Fan Z, Shang BY, Lu Y, Chou J-L, Mendelsohn J. Reciprocal changes in p27Kip1 and p21Cip1 in growth inhibition mediated by blockade or overstimulation of epidermal growth factor receptors [Advances in Brief]. Clin Cancer Res 3:1943-1948, 1997.
  20. Mandal M, Adam L, Mendelsohn J, Kumar R. Nuclear targeting of Bax during epidermal growth factor receptor-induced apoptosis in colorectal cancer cells. Oncogene 17:999-1007, 1998.
  21. Baselga J, Norton L, Albanell J, Kim Y-M, Mendelsohn J. Recombinant humanized anti-HER2 antibody (Herceptin™) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. Cancer Res 58:2825-2831, 1998.
  22. Ye D, Mendelsohn J, Fan Z. Augmentation of a humanized anti-HER2 mAb 4D5 induced growth inhibition by a human-mouse chimeric anti-EGF receptor mAb C225. Oncogene 18:731-738, 1999.
  23. Milas L, Mason K, Hunter N, Petersen S, Yamakawa M, Ang, K, Mendelsohn, J, Fan Z. In vivo enhancement of tumor radioresponse by C225 antiepidermal growth factor receptor antibody. Clin Cancer Res, 6: 701-708, 2000.
  24. Baselga J, Pfister D, Cooper MR, Cohen R, Burtness B, Bos M, D’Andrea G, Seidman A, Norton L, Gunnet K, Anderson V, Waksal H, Mendelsohn J. Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin. J Clin Oncol, 18: 904-914, 2000.
  25. Liu B, Fang M, Schmidt M, Lu Y, Mendelsohn J, Fan Z. Induction of apoptosis and activation of the caspase cascade by anti-EGF receptor monoclonal antibodies in DiFi human colon cancer cells do not involve the c-jun N-terminal kinase activity. Br J Cancer 82:1991-1999, 2000.
  26. Ciardiello F, Bianco R, Damiano V, Fontanini G, Caputo R, Pomatico G, De Placido S, Bianco AR, Mendelsohn J, Tortora G. Antiangiogenic and antitumor activity of anti-epidermal growth factor receptor C225 monoclonal antibody in combination with vascular endothelial growth factor antisense oligonucleotide in human GEO colon cancer cells. Clin Cancer Res, 6: 3739-3747, 2000.
  27. Albanell J, Codony-Servat J, Rojo F, Del Campo J, Sauleda S, Anido J, Raspall G, Giralt J, Rosello J, Nicholson R, Mendelsohn J, Baselga J. Activated extracellular signal-regulated kinases: association with epidermal growth factor receptor/transforming growth factor alpha expression in head and neck squamous carcinoma and inhibition by anti-EGF receptor treatments. Cancer Res, 61 (17): 6500-6510, 2001.
  28. Shin DM, Donato NJ, Perez-Soler R, Shin HJ, Wu JY, Zhang P, Lawhorn K, Khuri FR, Glisson BS, Myers J, Clayman G, Pfister D, Falcey J, Waksal H, Mendelsohn J, Hong WK. Epidermal growth factor receptor-targeted therapy with C225 and cisplatin in patients with head and neck cancer. Clin Cancer Res 7:1204-1213, 2001.
  29. 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.
  30. Mendelsohn J. David A. Karnofsky Award Lecture. Targeting the epidermal growth factor receptor for cancer therapy. J Clin Oncol 20(18s):1s-13s, 2002.
  31. Mendelsohn J and Baselga J: Status of EGF-receptor antagonists in the biology and treatment of cancer. J Clin Oncol (Biology of Neoplasia series). 21: 2787-2799, 2003.
  32. Onn A, Mendelsohn J and Herbst R: Targeting the epidermal growth factor receptor in the clinic. In V. T. Jr. DeVita, S. Hellman, and S.A. Rosenberg (eds.), Progress in oncology 2004, pp. 73-100. Boston Toronto London Singapore: Jones and Bartlett Publishers, 2004.
  33. Mendelsohn J and Baselga J: EGFR targeting in cancer. Seminars Oncol, 33(4):369-385, 2006.
Research Grants/Contracts

Principal investigator, Cancer Center Support Grant (The University of Texas M. D. Anderson Cancer Center), No. P30-CA16672-30, 07/01/03 through 06/30/2008, $47,406,781.

Co-principal investigator, The Breast Cancer Research Foundation Grant, The Breast Cancer Research Foundation, 10/01/2007 through 09/30/2008, $208,334.

Patents Granted/Drugs Approved

U.S. Patent 4,943,533, held by the University of California at San Diego, John Mendelsohn, M.D., co-inventor of C225 (ErbituxTM).

FDA approved ErbituxTM for the treatment of advanced colorectal cancer on February 12, 2004, and for head and neck on March 1, 2006.

© 2009 The University of Texas M. D. Anderson Cancer Center