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© 2002 American Society for Clinical Oncology
Targeting the Epidermal Growth Factor Receptor for Cancer TherapyByFrom the University of Texas M.D. Anderson Cancer Center, Houston, TX. Address reprint requests to John Mendelsohn, MD, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 91, Houston, TX 77030-4009; email: jmendelsohn{at}mdanderson.org
IN 1981 AT THE University of California, Dr Gordon Sato and I hypothesized that a monoclonal antibody that binds to epidermal growth factor (EGF) receptors and that can block the binding of either EGF or transforming growth factor-alpha (TGF-  ) might prevent cell proliferation by inhibiting the signal transduction pathways that depend on activation of the EGF receptor.1-3
The rationale behind this is worth reviewing, because there was evidence from a variety of sources that led us to this hypothesis. EGF had been identified as early as 1962, and its receptor was purified and characterized by Stanley Cohen in 1980.4,5 He received the Nobel Prize in Physiology and Medicine for this body of work a few years later. Also, in 1980, Dr Gordon Sato was completing a decade of research, demonstrating that serum is required for cells to grow in culture because it provides growth factors.6 In 1980, in a seminal paper, Sporn and Todaro7 put forth the autocrine hypothesis that cancer cells can bypass restrictions on their growth by producing their own growth factors and autostimulating receptors on the cell’s surface. In addition, there was the knowledge that circulating antibodies can block the function of receptors in people and produce disease (experiments of nature): in myasthenia gravis, circulating antibodies inhibit the acetylcholine receptor; there are forms of hyper- and hypothyroidism in which antibodies against thyroid-stimulating hormone inhibit or stimulate thyroid function; and there are rare forms of diabetes in which circulating antibodies against the insulin receptor can mimic diabetes.
In 1981, evidence was being reported that EGF receptors are overexpressed on cancer cells; subsequently, we have learned that one third of all epithelial cancers express high levels of EGF receptors, and in many cases, this correlates with a poor prognosis.8 Also in the early 1980s it was learned that the EGF receptor and src, one of the first well-characterized oncogenes, share the novel property of being a protein tyrosine kinase.9-11 Subsequently, the EGF receptor was identified as a cellular oncogene with homology to the v-erb-b viral oncogene, and experiments with gene transfer and with transgenic mice showed that overexpression of the EGF receptor can be a transforming event.12-15 These data suggested that if we could block the binding of EGF or TGF- In 1983 and 1984, my colleagues and I published a series of papers demonstrating that blockade of the EGF receptor with murine monoclonal antibody 225 could inhibit the proliferation of cells, both in culture and in human tumor xenografts.1,2,16 We also demonstrated that blocking this receptor inhibited its tyrosine kinase activity.3 This was the first example of an inhibitor of a tyrosine kinase that could produce inhibition of cell growth in culture and inhibition of tumor growth in vivo, and as far as I know, this was the first example of a targeted therapy against an oncogene product. Subsequently, other inhibitory antibodies have been produced against the EGF receptor, and a number of low-molecular-weight tyrosine kinase inhibitors have been synthesized which act intracellularly on the receptor by blocking the adenosine triphosphate (ATP) binding site. All of these have the same objective—to stop the signal transduction that is initiated by activating the EGF receptor. Also soon after our report, Drs Jeffrey Drebin, Mark Greene, and Robert Weinberg reported the first monoclonal antibody against HER-2 with antiproliferative activity, and this was soon followed by Genentech’s production of a monoclonal antibody against HER-2.17,18 Dr Dennis Slamon reported overexpression of HER2 in 25% to 30% of patients with breast cancer and led successful clinical trials with the humanized version of this antibody, known as trastuzumab (Herceptin; Genentech, South San Francisco, CA).19,20 C225, the human:murine chimeric antibody derived from murine monoclonal antibody 225, is an immunoglobulin G (IgG) molecule that can bind complement.21 C225 binds with high affinity to the EGF receptor, higher than the natural ligands. It competitively inhibits binding of the growth factor to its receptor and inhibits activation of the receptor tyrosine kinase. A number of other monoclonal antibodies have been produced against the EGF receptor. The first, R3, from Dr Michael Waterfield’s laboratory, does not block ligand binding and was explored clinically as a carrier targeting radioactive molecules to EGF receptor–bearing cells.22 ABX-EGF, EMD 72000, and h-R3 are monoclonal antibodies that act in a manner similar to C225.23-25 In addition, a number of bispecific antibodies are in clinical trials, where one arm of the antibody binds to the EGF receptor and the other arm binds either to lymphocytes or to the IgG receptor on monocytes and macrophages.26-28 The goal is to attract these immune and inflammatory cells to tumor cells bearing high levels of EGF receptors. A large number of low-molecular-weight, soluble molecules that act on the receptor intracellularly have been developed and are in clinical trials.29-38 These can be organized into four categories: EGF receptor specific and reversible, receptor specific and irreversible, and agents that bind to more than one receptor in the EGF receptor family, either reversible or irreversible (Table 1) (Mendelsohn and Baselga, manuscript submitted). Among these, ZD1839 and OSI-774 are in phase III trials and are submitted for review by the United States Food and Drug Administration, as is C225. In this review, I will focus on examples of research findings with these three agents.
First, let’s consider the mechanism of antitumor activity. Table 2 summarizes a "scorecard" that was published by Drs Douglas Hanahan and Robert Weinberg39 listing the characteristics and capabilities of a cell when it becomes malignant. The first of these is self-sufficiency in growth signals. Cancer cells produce their own growth factors and autostimulate themselves, and EGF inhibition blocks this capability. The second characteristic is insensitivity to antigrowth agents such as transforming growth factor-beta (TGF-ß), and EGF receptor inhibition reverses this characteristic. The third is evading apoptosis, and EGF receptor inhibition is proapoptotic. The fourth characteristic is unlimited replicative potential, related to telomerase. I know of no data to date that the EGF receptor signaling pathway interacts at all with telomerase. The fifth is sustained angiogenesis, and a large amount of data show that blocking the EGF receptor inhibits angiogenesis. Finally, tissue invasion and metastasis are inhibited by blocking EGF receptor activity.
I want to emphasize that it was only the first of these characteristics that Dr Sato and I were considering when we began to investigate EGF receptor blockade in 1981, and the rest of the beneficial effects of this approach have been discovered subsequently. So, there was serendipity in the selection of a target that now appears to have profound and widespread influences on the malignant process. Two other characteristics that I will add to the scorecard are shown in Table 2. EGF receptor inhibition can inhibit repair or recovery after chemotherapy or radiation. And, in the case of the monoclonal antibodies but not the other agents, there is the possibility of an immunologic attack on the target cell resulting from antibody binding.
I will present data demonstrating the effects of EGF receptor inhibition on these characteristics of human cancer. Figure 1 from Dr Jose Baselga demonstrates the inhibition of signaling pathways when EGF receptors are blocked with ZD1839.40 The cells in Fig 1 are the A431 squamous carcinoma cell line, which expresses high levels of EGF receptors and produces large amounts of TGF-
The inhibition of cell growth that results from EGF receptor blockade is characterized by G1 phase arrest. For example, in an experiment carried out by Dr Xipu Wu in my laboratory with DiFi colon carcinoma cells, the S phase fraction was 35% in control cells growing in culture and fell to 3% after 24 hours in the presence of antibody 225, with accumulation of nearly all cells in G1 phase.41 In a recent study by Dr Paul Harari with ZD1839 on cultured squamous head and neck carcinoma cell lines, there was a reduction of cells in S phase with an increase in the G1 phase fraction.42 Drs Wu and Zhen Fan in my laboratory first determined the molecular mechanism accounting for inhibition of cell proliferation.43 Figure 2 depicts results of an experiment with DiFi cells grown in culture for 24 hours either in the absence or in the presence of monoclonal antibody 225.44 Blockade of EGF receptor activity resulted in a marked increase in the amount of p27KIP1, an inhibitor of cyclin-dependent kinases. An assay of cyclin-dependent kinase–2 activity, measured by the ability of immunoprecipitates from cell lysates to phosphorylate histone as a substrate, showed marked inhibition after cells were cultured in the presence of C225. The lower panel in Fig 2 displays the levels of phosphorylated RB protein. In the actively proliferating control cells, most of the RB protein is in the hyperphosphorylated form, which releases transcription factors. In cells incubated with antibody 225 for 24 hours, most of the RB is in the hypophosphorylated state, which binds transcription factors. This same mechanism involving p27KIP1 has subsequently been shown to explain the growth inhibitory activity of Herceptin, as well as soluble EGF receptor inhibitors. It appears that p27KIP1 is a common pathway for inhibiting cell growth when the tyrosine kinase activity of receptors in the EGF receptor family is blocked.44
The second characteristic from the Hanahan-Weinberg scorecard is escape from inhibition by TGF-ß. It has always been an interesting mystery that TGF-ß has two different capabilities. One is growth inhibition, and the other is promoting activities that enhance tumorigenesis. Recent observations from the laboratories of Drs Julian Downward, Joan Massague, and others have helped to explain how a cell decides which of these pathways to follow.45,46 Normally, growth inhibition is one of the major functions of TGF-ß in epithelial cells. However, stimulation of the EGF receptor reduces growth inhibition through mechanisms involving MAP kinase and/or myc activation, and TGF-ß can now stimulate angiogenesis and invasiveness. This may provide one explanation for why tumor cells express high levels of EGF receptors. Agents that block the EGF receptor cause reduced activation of MAP kinase and myc, enabling TGF-ß to exert a growth inhibitory effect on the cancer cells. EGF receptors also appear to regulate apoptosis in cancer cells. Dr Rakesh Kumar, my collaborator for many years, performed an experiment with the DiFi colon carcinoma cell line, which has very low levels of both the apoptosis inhibitor BCl-2 and the proapoptotic molecule Bax.47 When these cells were incubated with C225 over a period of 48 hours, there was a steady increase in the amount of Bax, unopposed by BCl-2. The DiFi cells underwent apoptosis after 48 hours in culture. Most cells in growing culture are inhibited rather than killed when their EGF receptors are blocked. An experiment in Dr Zhen Fan’s laboratory examined caspases-8 and -9 in cultured DiFi cells.48 When the cells were exposed to ultraviolet radiation, caspases-8 and -9 were activated and the cells underwent apoptosis. When the cell cultures were exposed to monoclonal antibody C225, there was a rise in caspase-8 and in caspase-9 with comparable kinetics and levels, accompanied by apoptosis. In experiments with other cell lines, EGF receptor blockade produced a reduction in the levels of BCl-2. In a variety of experiments, proapoptotic molecules were potentiated and antiapoptotic molecules were depressed as a result of blocking the EGF receptor–signaling pathway. Turning to angiogenesis, experiments by Drs Robert Kerbel, Josh Fidler, Colin Dinney, and Robert Radinsky demonstrated profound effects of EGF receptor blockade.49-51 For example, Dr Dinney studied a bladder transitional cell carcinoma line. These cells were shown to produce large amounts of vascular endothelial growth factor (VEGF) in culture, and in the presence of C225, VEGF production was almost completely inhibited. In parallel, there was reduced production of interleukin-8 and of basic fibroblast growth factor. Thus, production of three pro-angiogenic molecules can be reduced or eliminated by blocking the EGF receptor. In vivo studies by Dr Dinney with orthotopic xenografts in nude mice demonstrated that treatment with C225 reduced tumor vasculature and caused reduction in the tumor cell content of VEGF, interleukin-8, and basic fibroblast growth factor.50
In a similar study by Dr Radinsky, mice bearing pancreatic xenografts were treated with either gemcitabine, the most active drug against pancreatic cancer, or C225 or both agents (Fig 3).51 The Texas red stain for CD31 shows vascular endothelial cells lining the blood vessels of the control xenografts. The green terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate-biotin nick end-labeling stain for terminal transferase shows few dead cells in the controls. In the gemcitabine-treated animals, apoptosis of tumor cells is increased. In the animals treated with C225 antibody, some apoptotic (green) tumor cells are seen, and some of the vascular endothelial cells are stained red for CD31 antigen. The yellow staining of vascular endothelial cells, produced by the green color superimposed on red, indicates that they are undergoing apoptosis. There are two potential explanations for this observation. In this study, the tumor cells in the treated animals produced fewer angiogenic factors, which may actually be survival factors for the new vascular endothelial cells.52 Alternatively, Dr Fidler has shown recently that when angiogenesis occurs in the presence of cancer cells secreting large amounts of TGF-
An experiment with the orthotopic bladder cancer xenograft model also exemplifies the antimetastatic effect resulting from inhibition of EGF receptors.50 Treatment of mice with well-established (30-day) tumors resulted in marked reduction in tumor growth compared with controls, and some mice were cured. Furthermore, metastases to the lungs and lymph nodes that were observed in the control mice were prevented in the treated mice. Compared with the untreated controls, tumors exposed to EGF receptor blockade contained markedly reduced amounts of matrix metalloproteinase 9. In 1987, Dr Michael Sela’s laboratory reported that another antibody against the EGF receptor (one that is not in clinical trials), when combined with cisplatinum, had additive or synergistic antitumor effects in a nude mouse model.53 This report stimulated the hypothesis that receptor blockade may augment the antitumor effects of conventional chemotherapy or radiotherapy. A great deal of data have accumulated, supporting this concept. One of the first studies in our laboratory was done by Dr Fan with well-established A431 squamous carcinoma xenografts (Fig 4). 54 When these tumors were treated either with 225 antibody alone, or with cisplatin alone at the maximum-tolerated doses, there were no responses, but when combined therapy was given, tumors were eradicated. Comparable results were obtained by Dr Jose Baselga, combining C225 with doxorubicin against A431 xenografts and with paclitaxel against MDA468 breast adenocarcinoma xenografts.55,56
An example of a similar study with ZD1839 comes from Dr Frank Sirotnik’s laboratory using xenografts of LX-1 squamous lung carcinoma cells (Fig 5).57 The response to ZD1839 in combination with paclitaxel far exceeds the response to either treatment alone.
Drs Fortunato Ciardiello and Giampaolo Tortora explored the combination of topotecan and C225 against xenografts of Geo colon carcinoma cells with similar results.58 Their extensive study of Geo xenografts treated with paclitaxel or ZD1839 or with combination therapy showed that the combination therapy enhanced tumor growth inhibition and achieved one cure among six xenografts.59 Furthermore, they documented marked reduction in the percentage of tumor cells that produced TGF- or VEGF in mice receiving ZD1839 treatment. Angiogenesis, assayed by counting the number of new blood vessels per microscopic field, was inhibited by 95% with the combination therapy. These examples from numerous preclinical studies with anti–EGF receptor agents demonstrate the potential efficacy of these therapies in cancer treatment, and clearly explain the rationale justifying their use in combination with chemotherapy. The results of clinical trials with thousands of patients support the promise of anti–EGF receptor therapy, and as noted, trials for accelerated approval with three of these agents have been submitted to the Food and Drug Administration. Results from some of the trials with C225, ZD1839, and OSI-774 will be summarized.
Following up on the preclinical observations, a critical clinical trial was carried out by Dr Dong Shin in patients with advanced head and neck cancer who had tumor progression on combination chemotherapy.60 Of nine assessable patients, six had a partial or complete response to treatment with C225 plus cisplatin. Remarkably, three of these six patients had previously received cisplatin and had experienced resistance while on this chemotherapy. When these patients were subsequently treated with a combination of cisplatin and C225, there were two complete responses and one partial response—an outcome that is very unusual after cisplatin failure. Figure 6 shows disappearance of subcutaneous metastases in one of these patients, and histologic examination of a biopsy demonstrated absence of free EGF receptors due to either receptor downregulation or receptor precoating with antibody C225. Receptor tyrosine kinase activity in tumor biopsy specimens was shown to be inhibited in these patients.
This clinical trial was followed with a phase II trial under Dr Waun Ki Hong in advanced pretreated head and neck cancer patients. Patients were placed on cisplatin therapy, and when cisplatin treatment failed as evidenced by tumor growth, C225 antibody was added in combination with continued cisplatin.61 Twenty-three percent of the patients had a partial response to the combination. The data from an expanded version of this trial were recently reported by Dr Merrill Kies, who found an 11.5% partial response rate.62 A phase II European study led by Dr Jose Baselga with a similar design and using cisplatin or carboplatin gave 12.5% partial responses and 2% complete responses, for a 14.5% overall response rate.63 A phase III Eastern Cooperative Oncology Group head and neck cancer trial randomized patients to receive cisplatin plus C225 or cisplatin plus placebo. Dr Barbara Burtness recently reported that while the improvement in time to progression (the primary end point) was only modest, patients on the C225 arm had a 22.6% objective partial response rate, compared with 9.3% in patients receiving cisplatin alone.64 A randomized trial with larger numbers of patients is planned. Many clinical trials have explored the use of EGF receptor inhibitors for the treatment of non–small-cell lung cancer. The most extensively studied agent is ZD1839. In a phase II trial carried out in Europe and Japan, the partial response rate was 19%.65 Interestingly, European responses were 11% whereas Japanese response rates were 27.5% for reasons that may relate to severity and extent of disease, differences in prior treatment, differences in male:female ratios and performance status, or differences in the number of adenocarcinomas. A recent phase II ZD1839 trial in the United States, reported by Dr Mark Kris, showed a partial response rate of 10%.66 Results are awaited from a large and fully enrolled randomized phase III trial of first-line chemotherapy (two alternative regimens) with ZD1839 or with placebo. A phase II trial in previously treated non–small-cell lung cancer has been carried out with OSI-774. The complete response rate was 2% and the partial response rate was 11%.35 In a phase II trial reported by Dr Edward Kim, treatment with C225 plus docetaxel resulted in a 26.7% partial response rate.67 C225 treatment has been explored in carcinoma of the colon. In a preclinical study carried out by Dr Dan Hicklin, HT29 colon carcinoma xenografts were treated with irinotecan.68 The tumors that failed to respond to irinotecan were then randomized for treatment with C225 alone, irinotecan alone, or a combination of C225 plus irinotecan. While 225 partially reduced the growth of the xenografts and irinotecan also partially reduced growth, the combination completely arrested tumor growth. The combination therapy also markedly reduced the proliferation index of cancer cells and enhanced apoptosis. A phase II clinical trial that followed this model was reported by Dr Leonard Saltz.69 In this case, patients with advanced colorectal cancer expressing EGF receptors were placed on irinotecan and followed. When progression on irinotecan was documented, the drug was continued and C225 antibody therapy was added. Of the 120 patients who had progressed on irinotecan, 22.5% achieved a partial response when C225 was added to the irinotecan. In a follow-up phase II trial conducted by Dr Saltz, patients with colorectal carcinoma whose irinotecan treatment failed were treated with single-agent monoclonal antibody C225, and an 11% partial response rate to C225 therapy was observed (L. Saltz, personal communication, April 2002). A randomized phase III trial treating colorectal carcinoma with irinotecan plus or minus C225 has been fully enrolled, and results are awaited.
Some interesting data came out of the phase II combination therapy trial.69 One can ask the question of whether high levels of EGF receptor expression are required for response to antireceptor therapy. The response rate in patients who had 1+, 2+, or 3+ levels of receptor expression in biopsy tissue from their tumors was around 22%, regardless of the level of EGF receptor expression. This is in contrast to the experience with Herceptin, the inhibitory monoclonal antibody that blocks HER-2. For Herceptin, a high, 3+ level of receptor expression is required for optimal response to second-line therapy, and in first-line therapy, nearly all of the responders were patients with breast cancer expressing high levels of HER-2. It is likely that the relevant criterion predicting a response to an EGF receptor inhibitor is the degree of dependence on the autocrine pathway, for which surrogate markers might be the level of receptor expression plus the level of production or EGF or TGF- Another interesting observation in Dr Saltz’s study relates to the major side effect of treatment with C225, an acneiform skin rash. Of the 27 responders in his study, 26 had a skin rash; only one responder did not have a skin rash. Thus, in this clinical trial, a skin rash appeared to identify patients whose cancers were more likely to respond to EGF receptor inhibition, although the majority of those with a rash did not respond. There are reports of laboratory studies suggesting that the combination of an EGF receptor inhibitor plus a biologic agent may have synergistic antitumor activity. Both Dr Carlos Arteaga and Dr Mark Moasser have shown that ZD1839 can inhibit proliferation of breast adenocarcinoma cell lines bearing EGF receptors as well as high levels of HER-2.70,71 Combination therapy with ZD1839 plus Herceptin produced enhanced antitumor activity, resulting in apoptosis of cultured cells. This is very interesting but not surprising, since the HER-2 receptor forms a heterodimer with the EGF receptor (or with HER-3) when it is activated. Another suggestion for combination therapy comes from Dr Christopher Torrance using mice that had been genetically altered by expression of an abnormal APC (adenomatous polyposis coli) gene.72 These mice develop pathology comparable to the human disease. In the untreated situation, there were 32 polyps per colon. In mice treated with EKB-785, a low-molecular-weight inhibitor of the EGF receptor tyrosine kinase, there was a 52% reduction in polyps. With sulindac, a cyclo-oxygenase 2 (COX-2) inhibitor, there was a 31% reduction in polyps. When EGF receptor inhibition was combined with COX inhibition, there was a 97% reduction in polyps (one polyp). There are ongoing clinical trials with COX-2 inhibitors in colon cancer, and there is a strong rationale for future trials combining an EGF inhibitor with a COX-2 inhibitor. EGF receptor blockade combined with radiation therapy has also been explored in preclinical experiments and in clinical trials. Dr Paul Harari has investigated head and neck squamous carcinoma cell lines growing in culture and in xenografts. The combination of radiation plus C225 or ZD1839 resulted in enhanced antitumor activity against xenografts.42,73 Similar results were reported by Dr Luka Milas in studies of radiation plus C225 treatment of A431 squamous carcinoma xenografts.74 The first clinical trial with radiotherapy plus C225 was reported recently.75 In this phase I/II study, radiation was combined with C225 in patients with advanced head and neck cancer. In these patients, the expected complete plus partial response rate to radiation therapy alone is 60% to 70%. In the clinical trial combining radiation with C225 treatment, 12 out of the 14 patients had complete responses, and one other patient converted to a complete response. At 19 months, 60% of these patients were still in complete remission. Accrual to a multi-institution, phase III trial, randomizing radiation with and without C225, has been completed and the results are awaited. Table 3 summarizes the main adverse events and side effects from 21 trials with C225 involving 813 patients (provided by ImClone Systems, Inc, New York, NY). Seventy-seven percent of patients experienced an acneiform rash, and 16% had a severe rash (grade 3 or 4). Less than 2% had an anaphylactoid or anaphylactic reaction, almost invariably after the first exposure to the antibody. Presumably this represents an inherent allergy to the mouse component of the protein in the antibody. Responses to administration of diphenhydramine hydrochloride, steroids, or in some cases epinephrine were prompt and complete. The side effect profiles for the oral anti–EGF receptor agents at doses determined to be the maximum-tolerated doses are similar to that shown in Table 3, with the exception that diarrhea is a more prominent side effect, presumably due to greater penetration of drug through the natural barrier in the gastrointestinal mucosa.65
In the trials with C225, 4% of the patients did produce circulating antibodies against the human:murine chimeric monoclonal antibody. These antibodies were nonneutralizing, and they did not change the pharmacokinetics of administered C225.76
EGF receptor–targeted therapies present opportunities and challenges for the future. We need to further explore schedules and combinations that optimize therapeutic results. Most studies to date have been on advanced disease, and it will be important—as with any new therapy—to see the results with early stages of disease.
The response rates in current studies with each of the anti–EGF receptor agents represent only a fraction of the patients treated. It would be preferable to identify markers that enable oncologists to preselect tumors that are likely to be responsive to EGF receptor inhibition. This is a challenge with all forms of cancer therapy that we use today. We need to obtain pretreatment tumor biopsy specimens to assess EGF receptor expression and phosphorylation, the levels of TGF- The only way to determine the comparative merits of the variety of new agents that block the EGF receptor activity is to perform clinical trials. The extracellular approach to EGF receptor blockade with a monoclonal antibody and the intracellular approach with an ATP binding site blocker have a great deal in common, and each approach has potential merits. The agents in the two classes differ in absolute specificity for the EGF receptor, the potential for dose-dependent toxicity, and the types of adverse events that have been reported. Also, the route of administration of antibodies is intravenous, whereas most of the agents that block the ATP binding site are administered orally. In 1997, Dr Monique Bos in my laboratory published a study showing that combined treatment with C225 antibody plus PD153035, an early soluble inhibitor of the EGF receptor, produced greater antitumor activity than either agent alone against a number of cultured cells lines.77 This suggests that clinical trials with a combination of anti–EGF receptor agents that involve different mechanisms of action should be performed in the future. In conclusion, we and others have shown that inhibitors of EGF receptor tyrosine kinase activation are active anticancer agents in the clinic. This approach to cancer therapy initiated the concepts of inhibiting tyrosine kinases and oncogene products, concepts that are rapidly being expanded to include numerous targets. There is strong evidence that combination treatment with an EGF receptor inhibitor plus either chemotherapy or radiation therapy produces enhanced antitumor responses. I believe this will be the major way that agents that block signaling pathways will be used in the clinic. The well-documented cross-talk between the key pathways that regulate cell cycle traversal, apoptosis, and processes such as angiogenesis and metastasis strongly suggests that combinations of new agents targeting one or more of these critical regulating pathways will enhance the efficacy of cancer therapy.
APPENDIX The appendix listing Dr Mendelshon’s former and current collaborators and trainees is available online at www.jco.org.
I would like to thank my mentors and collaborators. My research training began in the laboratory of Dr. James D. Watson in 1956. I was his first undergraduate student at Harvard College, and the term molecular biology was novel at that time. It is amazing what has happened in less than 50 years. Dr John Paul at the University of Glasgow taught me the mysteries of cell culture during my year as a Fulbright Scholar. Dr Byron Waksman at the Massachusetts General Hospital taught me experimental immunology. Dr Norman Salzman at the National Institutes of Health introduced me to the 1965 version of molecular biology, which had exploded in techniques and possibilities. Dr Stuart Kornfeld introduced me to translational laboratory research during my fellowship at Washington University. And the most important person to add to this list is Anne Mendelsohn, my wife since 1963, who is a fabulous mother and partner in everything we have done together at University of California San Diego, Memorial Sloan-Kettering Cancer Center, and The University of Texas M.D. Anderson Cancer Center. Thank you very much for the honor of the Karnofsky Award.
The author is a director and has financial interests in ImClone Systems, Inc, New York, NY, which has licensed the antibody C225 from the University of California. The author has never treated a patient with C225.
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), or 225 MAb, 1 mg/mouse, twice a week for 4 weeks, with (
) or without (
) two injections of cis-DDP (150 µg/25 g mouse weight) on days 8 and 18. Arrows indicate timing of drug and antibody treatment. Data are expressed as the mean tumor size ± SE (seven mice per group). (B) Mice were observed for 6 months for survival. Reprinted with permission.
