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The development of epidermal growth factor receptor-targeted therapies in gastrointestinal malignancies.

Epidermal growth factor receptor and tumour biology

In health, normal cellular growth and function is reliant on the maintenance of a complex equilibrium of stimulatory and inhibitory cellular signalling. In many malignant diseases this equilibrium is lost, resulting in the promotion of cell growth and proliferation, tissue invasion and metastasis, the evasion of apoptosis and sustained angiogenesis [1,2]. The epidermal growth factor receptor (EGFR) family is a key pathway that mediates cellular replication in response to growth factor stimulation. It is expressed in many human cancers and frequently associated with a more aggressive clinical course, making it a rational and novel target for anti-cancer therapy.

Epidermal growth factor (EGF) was first recognised in 1962 and the receptor was purified in 1980 [3]. As well as being expressed in healthy tissue such as skin, liver and gastrointestinal tract, it is over-expressed in several human malignancies--notably colorectal [4-6], pancreatic [7] and gastric cancers [8,9].

The EGF or ErbB receptor family is composed of four receptors; EGFR/ErbB1/HER1, ErbB2/HER2, ErbB3/HER3 and ErbB4/HER4. Each receptor consists of an intracellular tyrosine kinase domain, a transmembrane domain and an extracellular ligand-binding domain. Upon ligand binding, ErbB receptors form homo- or heterodimers leading to activation of the tyrosine kinase domain and the triggering of a complex downstream signalling cascade. HER3 differs in that it has little inherent tyrosine activity [10] and is reliant on heterodimerisation with other ErbB receptors for tyrosine phosphorylation. The main ligands for EGFR are EGF and transforming growth factor-alpha (TGF-[alpha]). There is no identified ligand for HER2, which is the preferred dimerisation partner for the other ErbB receptors [11].

Stimulation of EGFR leads to the activation of a number of downstream signalling pathways, including the mitogen-activated protein kinase (MAPK) and the phosphatidylinositol-3 kinase (PI3K) pathway, which mediate cell cycle progression, cell survival and proliferation [2].

EGFR is expressed in approximately 70-80% of colorectal tumours, 70-90% of oesophageal tumours and 30-50% of pancreatic tumours. EGFR expression is associated with high-stage disease in colon cancer and the presence of lymph-node metastases in gastric cancer, and expression is also associated with reduced relapse-free and overall survival in many gastrointestinal malignancies [12,13].

In view of these factors, EGFR inhibitors have been widely evaluated in gastrointestinal malignancies. Inhibition of EGFR may be achieved by a variety of mechanisms including utilising antisense or small interference RNA to suppress EGFR gene expression [14], the use of tyrosine kinase inhibitors that target the intracellular tyrosine kinase domain, or the use of monoclonal antibodies that target the extracellular domain and inhibit ligand binding. Of these, the small molecule tyrosine kinase inhibitors and monoclonal antibodies have been selected for therapeutic development.

Preclinical development of EGFR-targeted monoclonal antibodies

EGFR was first investigated as a therapeutic target over 20 years ago. Sato et al. created four mouse hybridomas that secreted monoclonal immunoglobulin G to EGFR and tested their activity in cancer cell lines. Three of the antibodies bound to the receptor with sufficient avidity to inhibit EGF-mediated fibroblast proliferation without mimicking the activity of endogenous EGF in other ways [15]. Further studies using human tumour xenografts in athymic mice demonstrated the ability of EGFR-targeted monoclonal antibodies to inhibit tumour growth in vivo [16]. These initial in vivo studies gave the first indication that response to EGFR-targeted therapy does not correlate with EGFR expression. Despite a 100-fold variance in receptor concentration between two epidermoid tumour cell lines, both were equally inhibited by the EGFR-targeted antibody [16]. Additionally, the antibodies tested were cytostatic in vitro but cytocidal in vivo, indicating that the host environment may also play an important part in defining anti-tumour activity. EGFR-targeted therapy is known to have anti-angiogenic effects [16,17] and there are in vitro data suggesting that cetuximab may also induce antibody-directed cellular cytotoxicity [18]. The relative importance of these mechanisms in achieving the overall anti-tumour effect of EGFR-targeted therapies remains unknown.

These early studies utilised murine monoclonal antibodies (225), which in view of the immunogenicity could not be used therapeutically in humans. To overcome this hurdle, chimeric monoclonal antibodies (C225, cetuximab) were developed for therapeutic use [19].

Pre-clinical studies of C225/cetuximab in colorectal tumour xenografts

In vivo studies in nude mice first demonstrated the anti-tumour activity of C225, and highlighted its ability to potentiate the activity of cytotoxic agents and possibly reverse chemoresistance [20]. Using human colorectal cancer tumour xenografts, the activity of C225 and irinotecan given either alone or in combination was evaluated. In the first experimental group, the combination of both agents demonstrated greater activity than either agent alone. In a further experiment, tumours that were resistant to irinotecan were selected and then challenged with either irinotecan or C225 given alone, or a combination of the two agents. C225 and irinotecan given in isolation demonstrated little intrinsic anti-tumour activity in this chemotherapy-resistant subgroup; however, the combination of both agents resulted in significant inhibition of tumour growth. Histological analysis showed a reduction in tumour proliferation and vasculature, and an increase in apoptosis. These pre-clinical data formed the basis for the clinical evaluation of cetuximab in combination with irinotecan, in irinotecan-refractory patients with colon cancer.

EGFR-targeted monoclonal antibodies in clinical use

Following from the development of cetuximab, further EGFR-targeted antibodies have been developed including panitumumab (ABX-EGF) [21], matuzumab (EMD72000) [22] and nimotuzumab (h-R3) [23]. Although all of these antibodies target the extracellular domain of EGFR they differ in their structure, affinity for EGFR and pharmacokinetics (see Table 1). These differences in antibody structure explain some of the variation in the side effects displayed by each agent. The chimeric antibody cetuximab contains a higher proportion of mouse protein and thus is associated with a higher incidence of hypersensitivity reactions. The side effect profile of nimotuzumab also differs from the other agents in that it is not associated with skin rash [24]. It is possible that the anti-tumour efficacy may also differ between each agent because of differences in antibody binding affinity, epitope specificity [24] and immunogenicity [18]; currently there are no clinical data to support this.

EGFR-targeted antibodies have demonstrated therapeutic activity in advanced colorectal cancer and are undergoing Phase II and III evaluation for other gastrointestinal indications. Ongoing research continues to focus on improving our understanding of the molecular mechanisms involved in response or resistance to EGFR-targeted antibody therapy.

The development of tyrosine kinase inhibitors in gastrointestinal malignancy

Another approach to inhibition of EGFR has been to target the intracellular tyrosine kinase component with small molecule inhibitors. A number of EGFR-targeted small molecule inhibitors have been developed; most notably gefitinib, erlotinib and lapatinib, all of which are 4-anilinoquinazoline compounds. Gefitinib and erlotinib are reversible inhibitors of EGFR. Lapatinib differs in that it inhibits both EGFR and HER2 and also has a slower dissociation rate of the inhibitor-receptor complex than the other 4-anilinoquinazoline compounds [25]. Many other reversible and irreversible small molecule inhibitors are undergoing clinical development [26-28].

Although these agents are designed to specifically inhibit the EGFR family, their specificity is generally lower than the monoclonal antibodies, leading to undesired inhibitory effects on other receptor tyrosine kinases. The notable differences between the tyrosine kinase and monoclonal antibody EGFR inhibitors are summarised in Table 2.

Pre-clinical studies of the small molecule inhibitors have shown promise for a number of gastrointestinal indications. In vitro and in vivo experiments undertaken utilising colorectal cancer cell lines have demonstrated synergistic activity for the combination of gefitinib and irinotecan [29]. In pancreatic cancer cell lines, gefitinib inhibited cell proliferation and completely inhibited EGF-induced cell proliferation. Gefitinib was also found to inhibit basal and EGF-induced anchorage-independent cell growth and invasion [30]. Further studies have demonstrated the ability of erlotinib to reduce cellular proliferation of pancreatic cells in vitro, and a significant survival advantage was demonstrated in mice that received erlotinib therapy, using a murine model of pancreatic adenocarcinoma [31].

In the clinical setting, the tyrosine kinase inhibitors have shown little single-agent activity in gastrointestinal malignancies. Erlotinib when given in combination with gemcitabine has demonstrated benefit in the treatment of pancreatic cancer, with combination therapy showing a survival advantage over gemcitabine alone [32]. The results of studies evaluating EGFR tyrosine kinase inhibitors in colorectal cancer have so far been disappointing, primarily because of problematic toxicities when these agents have been tested in combination with cytotoxic regimens. It is possible that the next generation of tyrosine kinase inhibitors with improved potency and specificity may show greater efficacy and clinical utility in the treatment of gastrointestinal malignancies.


The story of the discovery of EGF, the identification of its role in cancer, and the development of agents targeting components of the EGFR pathway demonstrates a new paradigm for targeted therapeutic discovery and development. However our understanding of the complex molecular mechanism involved in defining treatment response or resistance to these agents remains limited. The therapeutic benefit of EGFR-targeted agents has been clearly demonstrated; ongoing work will aim to optimise the therapeutic gains that may be achieved through the targeting of this pathway.


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Christopher Jackson

Department of Medicine, Royal Marsden Hospital, London and Sutton, UK

Correspondence to: Christopher Jackson (email:
Table 1: Characteristics of epidermal growth factor receptor

Antibody Type Affinity Half-life
 ([k.sub.d]) (hours)

Matuzumab Humanised MoAb IgG1 0.01 nM 94-180

Nimotuzumab Humanised MoAb IgG1 1 nM 240

Cetuximab Chimeric MoAb IgG1 0.39 nM 75-95

Panitumumab Human MoAb IgG2 50 pM 305-458

Antibody Development in gastrointestinal cancers

Matuzumab Phase II: Evaluation in oesophago-gastric cancer [28]

Nimotuzumab Phase II: Evaluation in pancreatic cancer [23]

Cetuximab Phase III: Approved for use in chemorefractory
 colorectal cancer

Panitumumab Phase III: Approved for use in chemorefractory
 colorectal cancer

[K.sub.d], dissociation constant; MoAb, monoclonal antibody: IgG1/IgG2,
immunoglobulin G1 or G2.

Table 2: Characteristics of epidermal growth factor
receptor (EGFR)-targeted small molecule inhibitors
and antibody agents.

 Tyrosine kinase EGFR-targeted
 inhibitors antibodies

Delivery Oral Intravenous

Target specificity Low High

Toxicities Skin rash; diarrhoea Skin rash; infusion
 Dose limiting reactions
 Not dose limiting

Mechanism Signalling inhibition Signalling
of action inhibition;
 ? immune mediated
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Author:Jackson, Christopher
Publication:Advances in Gastrointestinal Cancer
Geographic Code:4EUUK
Date:Jun 1, 2007
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