AUTHOR AND EDITOR INFORMATION

Section 1 of 8  

• Authors and Editors
• Introduction
• Epidermal Growth Factor Receptors
• Epidermal Growth Factor Receptor Inhibitors
• Summary
• Interleukin, Cyclooxygenase-2, Carcinoembryonic Antigen, and Targeted Genetics
• Multimedia
• References

INTRODUCTION

Section 2 of 8  

• Authors and Editors
• Introduction
• Epidermal Growth Factor Receptors
• Epidermal Growth Factor Receptor Inhibitors
• Summary
• Interleukin, Cyclooxygenase-2, Carcinoembryonic Antigen, and Targeted Genetics
• Multimedia
• References

Despite advances in diagnostic and treatment modalities, the survival rate associated with head and neck cancer has not improved over the past 25 years. With the increased understanding of molecular mechanisms and basic pathways in the pathogenesis of squamous cell cancer of the head and neck, these pathways may be modified, and rational approaches in cancer therapy at the molecular level may be created. Treatment intensification with concurrent chemoradiotherapy has been shown to increase the chance of survival and improve organ preservation over radiotherapy alone in patients with a locally advanced tumor, but at a cost of increased long-term toxicity. Chemotherapy and radiotherapy are limited by their lack of specificity. Molecular medicine and molecular therapy in head and neck cancer are the next important steps in treatment in the next decade.

Chemotherapy and radiation kill predominantly proliferating cells and do not discriminate between tumor cells and normal host cells. Some of the new approaches depend on tumor biology and aim specifically to inhibit tumor growth and metastasis by targeting the tumor microenvironment or vasculature (leaving normal cells unaffected) or focusing on specific protein or signal transduction pathways.¹ Targeted molecular therapy, similar to therapy with monoclonal antibodies (MAbs), gene therapy, and other therapies, has limited or nonexistent side effects on normal cells of the body, unlike present modalities such as surgery, chemotherapy, and radiotherapy. Targeted molecular therapy can also act as a complement to other existing cancer therapies.

The ideal target

Molecular physicians and researchers have discovered differences between cancer cells and normal cells. These differences led to the discovery of the targets that are only found on cancer cells and not in normal tissue and those targets that are differentially overexpressed in tumor cells compared to normal tissue. Other new modalities for treatment of head and neck squamous cell carcinoma (HNSCC) are modulation of cell cycle control, modulation of angiogenesis/hypoxia, and immune modulation and gene therapy. Not all molecules are good targets for cancer therapy at the molecular level.

The ideal target should have properties such as the following:

• Commonly found on cancer cells
• Differentially expressed or differentially functional in tumor versus nontumor host tissues
• Specific to cancer cells
• Causally related to tumor cell viability, progression, or both
• Involved in several aspects of the carcinogenesis pathway
• Measurable in diagnostic tumor material

Measurement of the target should provide some predictive information about the potential clinical response to the molecular targeted drug. The target, at some level, should validate mechanisms of resistance. Drug-mediated modulation of the molecular target should be validated in vivo.

Recently, drugs such as the HER-2 antibody trastuzumab and the Bcr-Abl tyrosine kinase inhibitor STI-571 have been approved for routine usage in clinical practice. The MAb trastuzumab was one of the first targeted agents to be approved for cancer therapy. Trastuzumab binds to and blocks ERBB2, also known as HER-2/neu, a cell-surface receptor of the epidermal growth factor receptor (EGFR) family. Overexpression of EERB2 occurs in approximately 25% of breast cancers and is associated with a poor patient prognosis. At present, trastuzumab is approved, alone or in combination with paclitaxel, for the treatment of metastatic breast cancer.

Targets already used for head and neck cancer in animal models include EGFRs, interleukin-13 receptor (IL-13R), protein kinase activator, and others that are in various phase I, II, and III studies.

For further information, please see Medscape’s Hematology-Oncology resource center.

EPIDERMAL GROWTH FACTOR RECEPTORS

Section 3 of 8  

• Authors and Editors
• Introduction
• Epidermal Growth Factor Receptors
• Epidermal Growth Factor Receptor Inhibitors
• Summary
• Interleukin, Cyclooxygenase-2, Carcinoembryonic Antigen, and Targeted Genetics
• Multimedia
• References

Advanced understanding of intracellular signaling processes responsible for transformation and tumor progression has enabled identification of potential therapeutic targets. The HER (erbB) family of receptor tyrosine kinases is one of the cytostatic targets in tumor cell growth and survival. The HER (erbB) family of transmembrane receptor tyrosine kinases plays a pivotal role in normal cell growth, lineage determination, repair, and functional differentiation. Overexpression of EGFR is recognized in more than 80% of squamous cell cancers, and this overexpression is associated with a poor prognosis.

Targeted molecular therapy against EGFR has shown promise as an adjuvant therapy in preliminary studies in several solid tumors, including head and neck cancer. Selective compounds have been developed that target either the extracellular ligand-binding region of the EGFR (including a number of MAbs, immunotoxins, and ligand-binding cytotoxic agents) or the intracellular tyrosine kinase region. This therapy interferes with adenosine triphosphate (ATP) binding to the receptor. ATP binding causes autophosphorylation and triggers a signaling network that results in tumor cell proliferation, angiogenesis, motility, metastasis, and protection from apoptosis. Agents that target the intracellular tyrosine kinase region include small molecule tyrosine kinase inhibitors.

The role of EGFR in transforming signaling network

The EGFR (also known as HER-1 or ERBB1) is a ubiquitous glycoprotein that contains a tyrosine kinase domain and a carboxy terminal (C terminal) region that contains critical tyrosine residues and receptor regulatory motifs. Binding of ligands to the extracellular domain results in receptor oligomerization, activation of the receptor's tyrosine kinase activity, and receptor autophosphorylation in several C terminal tyrosine residues.² These phosphorylated tyrosines serve as binding sites for a number of cytoplasmic signal-transducing molecules. The activation of these pathways downstream of the EGFR leads to cell proliferation, differentiation, and migration or motility and adhesion, protection from apoptosis, enhanced survival, and gene transcription.³

Targeting the HER/EGFR family

The HER family consists of 4 closely related transmembrane receptors: HER-1/EGFR, HER-2, HER-3, and HER-4. These receptors are structurally similar but have unique characteristics that dictate their signaling specificity. Each receptor has an extracellular ligand-binding domain, a transmembrane region that anchors the receptor to the cell, and an intracellular cytoplasmic domain that contains a tyrosine kinase region and a C terminal tail (see Image 1).⁴

The specificity and potency of the signaling output from activated EGFR is highly dependent on the type of activating ligand as well as on the cellular levels of coreceptors such as HER-2/neu (ERBB2), HER-3/neu (ERBB3), and HER-4/neu (ERBB4). These coreceptors can oligomerize with the EGFR. Several combinations of activation of receptors ultimately generate effective synergistic actions that lead to optimum signal transduction and tumor progression. Hence, blockade of this network yields maximum results.

Evidence linking EGFR with cellular transformation and tumor progression

EGFR function is essential for embryogenesis and organogenesis.⁴ Mice lacking the EGFR gene have severely impaired development of multiple organs, including the skin, brain, lung, kidney, liver, intestinal epithelium, and eye.⁵ These mice survive for only a short time after birth. In adults, EGFR has an important role in the repair of some epithelia, as supported by the skin and gastrointestinal toxicity observed in trials with EGFR inhibitors.^{6, 5} Both normal cells and cancer cells rely on EGFR signals, but in normal cells, the signal is strictly regulated (see Image 2).

Overexpression of the EGFR tyrosine kinase has been documented across all stages of disease, including precancerous lesions, early cancers, and advanced cancers. Some ductal carcinomas in situ, precursor lesions to invasive breast carcinoma, express high levels of EGFR tyrosine kinase. Increased expression of the EGFR and transforming growth factor–alpha (TGF-a) has been documented in early stage non–small-cell lung cancer (NSCLC) and in premalignant bronchial biopsy samples. These studies suggest that, pending information on the lack of chronic, long-term toxicity from use of EGFR tyrosine kinase inhibitors, these drugs may be used in the prevention of invasive cancers in high-risk populations (chemoprevention).

In light of a relationship between overexpression of EGFR and clinically aggressive malignant disease, EGFR has emerged as a promising target for treatment of patients with HNSCC. The identification of HER-1/EGFR as an important receptor in the pathogenesis of human tumors has prompted considerable research, focusing particularly on the HER family signaling network. Dysregulation of HER-1/EGFR activity can occur because of several mechanisms, including receptor overexpression, ligand overproduction, the presence of constitutively active receptor mutants, and cross-talk with other amplified receptors and signaling systems, among others. Increased understanding of the structure and function of these receptors has led to the development of various molecular targeted agents, such as MAbs and small-molecule tyrosine kinase inhibitors.

Rationale and strategy for targeting the EGFR network

The coexpression of EGFR and ligands at tumor sites allows for EGFR activation via autocrine/paracrine mechanisms. In support of the operational nature of these signaling pathways in EGFR-expressing tumor cells, interruption of signaling with various EGFR inhibitors has been shown to inhibit tumor cell proliferation and/or viability both in vitro and in vivo.⁷ These observations, in combination with (1) the ability to identify EGFR-expressing human tumors in diagnostic tissue from patients, (2) the association of EGFR overexpression with poor patient prognosis, and (3) the lack of a critical physiologic role of EGFR in healthy adults, have all suggested this network as an ideal target for novel therapeutic strategies.

Various MAbs have been studied to block EGFR at extracellular sites. Apart from blockade of EGFR signaling, EGFR antibodies may recruit Fc receptor–expressing immune effector cells; this leads to antibody-dependent cellular cytotoxicity and tumor lysis. However, high EGFR expression is not a predictor of tumor response to antitumor therapies.⁸ Another strategy is the blockade of intracellular ATP binding and tyrosine kinase function. Several small-molecule inhibitors of the EGFR tyrosine kinase are currently in clinical development and have been reviewed elsewhere. The Food and Drug Administration (FDA) has already approved the quinazolines ZD 1839 (Iressa) and OSI-774 (Tarceva) for clinical use. Both inhibit the purified EGFR tyrosine kinase enzyme in vitro with an inhibitory concentration of 50% (IC₅₀) in the low nanomolar range.⁸

Because of the high intracellular concentration of ATP, higher concentrations of these inhibitors are required to block EGFR phosphorylation continuously in intact cells (in vivo) than to inhibit the purified EGFR tyrosine kinase in vitro. At present, predicting which of the 2 strategies will be more effective is difficult. A molecule that has dual action would be ideal.⁸ The strong points of each are listed below:

• Humanized EGFR antibodies
• • Prolonged half-life
  • Some cytolytic actions by immune mediated pathways
  • Can induce receptor down-regulation
  • No gastrointestinal toxicity
• Low–molecular-weight EGFR tyrosine kinase inhibitors
• • Long-term therapy with oral administration
  • Can inhibit EGFR-homologous kinases such as HER-2
  • Can directly inhibit HER-2
  • Less potential for anaphylaxis or allergic reactions
  • Can inhibit mutant EGFRvIII kinase found in some tumors

EPIDERMAL GROWTH FACTOR RECEPTOR INHIBITORS

Section 4 of 8  

• Authors and Editors
• Introduction
• Epidermal Growth Factor Receptors
• Epidermal Growth Factor Receptor Inhibitors
• Summary
• Interleukin, Cyclooxygenase-2, Carcinoembryonic Antigen, and Targeted Genetics
• Multimedia
• References

Mechanisms of action of epidermal growth factor receptor inhibitors and clinical applications

Members of the HER family are established therapeutic targets for the development of novel anticancer agents, and several approaches are being used to block these receptors. The blockade may be by antibodies directed to extracellular binding sites or to intracellular sites of the EGFR (see Image 2).

Extracellular blockade

This strategy uses antibodies to block the extracellular ligand-binding region of the receptor. Two anti–HER-2 MAbs, trastuzumab (Herceptin; Genentech, Inc) and 2C4 (pertuzumab), with different epitopes, have been developed.

Trastuzumab

Trastuzumab is the first example of a successful HER-targeted agent that proves the principle of molecular targeted therapies in human breast cancer. It acts against HER-2–overexpressing tumors, in part by inducing receptor endocytosis.⁹ HER-2 is amplified in approximately 25-30% of human breast cancers.¹⁰ Clinical trials have shown that trastuzumab provides clinical benefits as significant as those monotherapy provides and improves the chance of survival when used in combination with chemotherapy as compared to chemotherapy alone in women with metastatic breast tumors that overexpress HER-2.^{11, 12}

Pertuzumab 2C4

Pertuzumab 2C4 is a recombinant humanized monoclonal antibody that binds to extracellular domain II of the HER-2 receptor and inhibits its ability to dimerize with other HER receptors. Pertuzumab 2C4 represents a novel class known as HER dimerization inhibitors. Agus and coworkers conducted a clinical study in 2005 to investigate its safety and pharmacokinetics and to perform an assessment of HER dimerization inhibition as a therapeutic strategy. Their results demonstrated that pertuzumab is well tolerated, has a pharmacokinetic profile which supports 3-week dosing, and is clinically active.¹³ Therefore, this study suggested that inhibition of dimerization may be an effective anticancer strategy.

Another study indicated that this unique mechanism of action could result in efficacy against tumors with low HER-2 expression that would not be targets for trastuzumab treatment.⁸

Anti–HER-1/EGFR

Several anti–HER-1/EGFR MAbs are also in clinical development. Cetuximab (Erbitux) is a humanized anti–HER-1/EGFR MAb that is extensively studied in targeted therapy of head and neck, lung, and colorectal cancer.

Cetuximab C225 (Erbitux, Imclone Systems Inc, New York) is a humanized immunoglobulin G (IgG)anti–HER/EGFR MAb directed against the extracellular ligand-binding domain of HER-1/EGFR. Phase I studies showed that cetuximab binds to HER-1/EGFR with an affinity comparable with that of the natural HER-1/EGFR ligands, epidermal growth factor (EGF) and TGF-<font face="symbol">a. This high-affinity binding of cetuximab to HER-1/EGFR prevents ligand binding and subsequent receptor activation. Several phase II clinical trials of cetuximab in combination with chemotherapy, radiotherapy, or both have been completed for a range of indications, including NSCLC, HNSCC, and colorectal cancer.^{14, 15, 16, 17, 18, 19} The FDA has recently approved this drug for clinical use.

Experiments suggest that the enhanced antitumor activity observed when C225 is combined with radiation derives not only from inhibiting proliferation but also from inhibiting several important processes, including DNA repair after exposure to radiation and angiogenesis.²⁰

The most frequently reported C225-related adverse events were asthenia, fever, and nausea (flulike symptoms) as well as elevated transaminases and allergic reactions. Acneiform rash and allergic reactions were clinically relevant. Eighty percent of patients developed rashes in the form of sterile folliculitis that usually affected the face, upper chest, and/or back. These rashes were usually mild to moderate in severity and resolved without treatment. Significant infusion reactions were uncommon but can be severe. The allergic reactions and anaphylactic reactions were rare and usually appeared within minutes of starting the initial infusion; were responsive to standard treatment; and could be prevented with the prophylactic administration of antihistamines, a prolonged infusion duration, or both.²¹

Intracellular blockade

Tyrosine kinase inhibitors

A second antireceptor approach is based on the observation of mutations in the ATP-bikinase function, which suggest that the receptor's tyrosine kinase is critical for EGFR-mediated tumor progression. HER-targeted agents acting at an intracellular level are low–molecular-weight tyrosine kinase inhibitors. The oral therapeutic agents OSI-774 (Tarceva) and ZD 1839 (Iressa) are selective EGFR tyrosine kinase antagonists that competitively inhibit binding of ATP to the intracellular domain of the EGF receptor (see Image 2), causing inhibition of ligand-induced cell growth by hindering autophosphorylation, leading to dose-dependent tumor stasis and even tumor regression. OSI-774 was initiated in the setting of recurrent and/or metastatic head and neck cancer.^{21, 22} Adverse effects of both include acneiform rash (72%), diarrhea, and fatigue.

Many of these small molecules are being investigated in clinical trials. Two agents that the FDA has recently approved are erlotinib and gefitinib (Iressa; AstraZeneca, Wilmington, Del). Tyrosine kinase inhibitors have the theoretical advantage of also blocking activating cytoplasmic signals when compared to agents that block activation at an extracellular level (ie, receptor MAbs). Interestingly, limited preclinical data suggest that erlotinib, but not gefitinib, can inhibit EGFR.^{23, 24} However, these preliminary data require confirmation. Whether this difference between the agents, if true, is caused by differences in structure or potency or other, as yet unknown, cell type–dependent factors is unknown. In addition, these agents are administered orally, which makes them suitable for long-term therapy.

Extensive preclinical studies with erlotinib and gefitinib show that both agents effectively inhibit tumor cell growth when used alone and in combination with various chemotherapeutic agents, and both are well tolerated.^{25, 26, 27, 28, 29, 30}

Recent results highlight the notion that preclinical studies of targeted agents, particularly in combination with other agents, may not be good predictors of clinical response. Therefore, to optimize the use of these agents, alternative approaches are being explored. One favored avenue of exploration is selecting responsive patients before therapy based on a predictive marker of response. A model for this approach involves trastuzumab; patients are selected for therapy based on the level of tumor HER-2 overexpression. This approach was obvious for trastuzumab because preclinical studies consistently showed that HER-2–overexpressing tumor cells, but not those with low HER-2 levels, were sensitive to trastuzumab-induced growth inhibition.

In contrast, preclinical and clinical studies have not found a strong correlation between HER-1/EGFR level and response to HER-1/EGFR-targeted therapies (Moasser, 2001). This suggests that patient selection for trials with these agents should not be based solely on HER/EGFR expression. Numerous studies are in progress to identify markers that may predict for response to HER-1/EGFR inhibitors.

SUMMARY

Section 5 of 8  

• Authors and Editors
• Introduction
• Epidermal Growth Factor Receptors
• Epidermal Growth Factor Receptor Inhibitors
• Summary
• Interleukin, Cyclooxygenase-2, Carcinoembryonic Antigen, and Targeted Genetics
• Multimedia
• References

The role of targeting EGFR in head and neck cancer

Preclinical and early clinical data from trials with erlotinib and other agents show that these inhibitors are well tolerated and could benefit patients with a variety of cancers. When data with other agents become available, their clinical application will become clearer, and new questions and challenges will emerge. Further understanding of the HER family signaling pathways and their interactions with other networks within tumor cells is necessary to optimize the clinical development of these targeted agents. Finally, a predictive marker that may help select patients for treatment with HER-1/EGFR inhibitors is sorely needed to maximize the information derived from ongoing studies.

Preliminary results from early clinical trials of both anti-EGFR MAbs and EGFR small-molecule tyrosine kinase inhibitors are promising. The rapid evaluation of these target-specific noncytotoxics is limited by the lack of accurate information concerning the relevance of target expression and its modulation to this tumor type. Early clinical trials are being designed to address these concerns. Current research goals include (1) defining the optimal dose and schedule in combinations with conventional chemotherapeutic agents and radiation therapy and (2) determining predictive factors that identify the best patient population in which to study and administer these agents. However, the clinical impact of EGFR inhibitors in patients with HNSCC must await the completion of randomized evaluations in combination with standard radiation and chemotherapeutic regimens.

Summary of the trials of targeted therapy usage in head and neck oncology

Despite various advances in research and newer molecules in chemotherapy, the survival rate in locally advanced or metastatic head and neck cancer has not improved over the past 25 years. Concurrent chemoradiotherapy increases survival and improves organ preservation over radiotherapy alone but with increased long-term toxicity. Also, concurrent chemoradiotherapy lacks specificity, affecting normal tissues along with tumor cells. Hence, newer modalities are being tried; these modalities use tumor biology specifically to inhibit tumor growth and metastasis by targeting the tumor microenvironment or vasculature (leaving normal cells unaffected) or by focusing on specific protein or signal transduction pathways.

The EGFR is a member of the ErbB/HER family of receptor tyrosine kinases, which also includes HER2, HER3, and HER4. EGFR is expressed in more than 90% of head and neck cancers, and its overexpression is associated with decreased survival. This overexpression is an early event in carcinogenesis and is even present in premalignant lesions. Hence, some rationalized that molecules could be used to specifically target this receptor. The main classes of drugs that are being studied are anti-EGFR monoclonal antibodies and EGFR-tyrosine kinase inhibitors. 

Anti-EGFR monoclonal antibodies

Cetuximab (C225), the most widely studied monoclonal antibody, is a chimeric antibody that binds to the ligand site of the EGFR. This blocks ligand binding, dimerization, and leads to downregulation of the receptors. In preclinical studies, cetuximab has been shown to have significant inhibitory effects on the EGFR receptor and the downstream pathways that it activates.

In a phase II trial, Herbst et al found better disease control rates and improved overall survival in both patients with stable disease and those patients with progressive disease following 2 cycles of cisplatinum-based chemotherapy.³¹ 

In a study of 96 patients with refractory progressive head and neck cancer, Baselga et al found a response rate of 10% with a disease control rate of 53% and improved median time to progression and overall survival.³² 

Data presented at the American Society of Clinical Oncologists in 2007 by Vermorken et al showed that patients with recurrent or metastatic head and neck cancer were randomized to receive cetuximab plus cisplatin (or carboplatin) and 5-fluorouracil (5-FU) or chemotherapy alone with promising initial results.³³ Kies et all conducted a phase II trial of induction chemotherapy using paclitaxel, carboplatin, and cetuximab in treatment-naïve patients with head and neck cancer followed by local treatment with good response and acceptable toxicity.³⁴ 

The Erbitux in First-Line Treatment of Recurrent or Metastatic Head and Neck Cancer (EXTREME) study is a European multicenter phase III trial presented at the American Society of Clinical Oncologists in 2007. The results showed that adding cetuximab improves the impact of platinum-based chemotherapy. Patients treated with cetuximab survived a median of 10.1 months compared with 7.4 months for those patients who receive chemotherapy alone. 

In a phase I dose-escalation study of erlotinib combined with docetaxel and radiation in locally advanced head and neck cancer, Savvides et al found no significant pharmacokinetic interactions between erlotinib and docetaxel and concluded that this regimen is feasible and active.³⁵ Kim et al studied the therapeutic effects of cisplatin, docetaxel, and erlotinib in advanced head and neck cancer and found an overall response rate of 66%.³⁶

A phase I/II trial by Doss that used induction chemotherapy plus gefitinib followed by concurrent chemotherapy/radiation/gefitinib for locally advanced head and neck cancer had an overall recurrence rate of 85% with improved progression-free survival (68%) and improved overall survival at 1 year (86%).³⁷

The additive effects of TKI and cetuximab were studied by Jimeno et al, who concluded that cetuximab interferes with erlotinib induced EGFR upregulation, resulting in antitumor effects.³⁸

Lapatinib (GW572016) is a selective and potent dual competitive inhibitor of EGFR and HER2. Harrington et al conducted a phase I study of lapatinib (dose escalation) plus chemoradiation (using cisplatin) in patients with locally advanced head and neck cancer with preliminary evidence of clinical activity.³⁹ Abidoye et al found no significant clinical response in their phase II study of lapatinib was evaluated in patients with recurrent/metastatic head and neck cancer.⁴⁰

VEGF inhibitors

Vokes et al, in a study of erlotinib with bevacizumab, showed stable disease in 31 of 44 patients with improved median progression-free survival and overall survival.⁴¹ Seiwert et al showed no major synergistic toxic effect in a phase I study of bevacizumab and 5-FU and hydroxyurea with concomitant radiotherapy for poor-prognosis head and neck cancer.⁴²

COX-2 inhibitors

Increased synthesis of COX-2–derived prostanoids leads to carcinogenesis. Limburg et al demonstrated the chemopreventive effect of Celecoxib in oral precancers and cancers in animal models.⁴³ Prellop et al conducted a phase IB/II trial to evaluate the toxicity and efficacy of celecoxib administered concurrently with CTRT (cisplatin, paclitaxel) for locally advanced or recurrent head and neck cancer.⁴⁴ The study was temporarily suspended in December 2004 because of the cardiotoxic effects of COX-2 inhibitors but was restarted with a modified schedule in May 2006 because of the initially promising results.

INTERLEUKIN, CYCLOOXYGENASE-2, CARCINOEMBRYONIC ANTIGEN, AND TARGETED GENETICS

Section 6 of 8  

• Authors and Editors
• Introduction
• Epidermal Growth Factor Receptors
• Epidermal Growth Factor Receptor Inhibitors
• Summary
• Interleukin, Cyclooxygenase-2, Carcinoembryonic Antigen, and Targeted Genetics
• Multimedia
• References

Interleukin

In 2002 and 2003, Kawakami et al found that, although IL-13R are overexpressed on several head and neck cancer cell lines, most cell lines express only low levels of IL-13R.^{45, 46, 47} They found that the primary interleukin-13–binding protein IL-13Ra2 chain plays an important role in ligand binding and internalization. They showed that the gene transfer of IL-13Ra2 chain into various solid-tumor cell lines that express few IL-13Rs could dramatically sensitize cells to the cytotoxic effect of a recombinant chimeric protein composed of interleukin-13 and a mutated form of Pseudomonas exotoxin A, IL13-PE38QQR.

By plasmid-mediated stable gene transfer, not only IL-13Ra2 chain–positive head and neck cancer cell lines, but also IL-13Ra2 chain–negative cell lines, can dramatically increase sensitivity to interleukin-13 toxin. Their results demonstrated that by using a combination approach of gene transfer and systemic or locoregional cytotoxin therapy, the IL-13R represents a new potent target for head and neck cancer therapy.^{46, 47}

Cyclooxygenase-2

Cyclooxygenase-2 (COX-2) is overexpressed in several premalignant and malignant mucosal conditions of the head and neck. Increased levels of COX-2 may contribute to carcinogenesis by modulating xenobiotic metabolism, apoptosis, immune surveillance, and angiogenesis. Newly developed, selective COX-2 inhibitors suppress the formation of tumors in experimental models. This may be a rationale for chemoprevention trials that are already underway.⁴⁸ In experimental animals, these also modulate the anticancer activity of radiotherapy and chemotherapy. Selective COX-2 inhibitors suppress the growth and metastases of established tumors.

A constant feature of anaplastic thyroid carcinoma that is currently a target for molecular target therapy is the inactivation of the TP53 gene. In 2002, Portella evaluated a therapeutic approach based on a gene-defective adenovirus (ONYX-015) that replicates only in cells with impaired TP53 function and leads to cell death.⁴⁹ They reported that the ONYX-015 virus induces cell death in 3 anaplastic thyroid carcinoma cell lines. The ONYX-015 virus worked synergistically with 2 antineoplastic drugs (doxorubicin and paclitaxel).

Carcinoembryonic antigen

Human carcinoembryonic antigen (CEA) is an oncofetal glycoprotein overexpressed in many gastrointestinal carcinomas. Expression of CEA in head and neck cancer is not widely recognized. Immunohistochemical analysis of tumor tissue from 69 cases of squamous cell carcinoma (SCC) of the head and neck using a CEA-specific MAb showed most to be positive for CEA. These results suggest that CEA may be considered as a possible target for specific vaccine-mediated immunotherapy against HNSCC.⁵⁰

Targeted genetics

Targeted genetics research has confirmed the results of preclinical studies that suggested that E1A has multiple cancer-fighting effects. One of these properties is the ability to down-regulate the oncogene for HER-2/neu. Importantly, overexpression of HER-2/neu occurs in a significant number of cancers. The level of HER-2/neu expression correlates with poor prognosis, increased metastasis, and resistance to chemotherapeutic agents. By reducing or inhibiting the expression of oncogenes such as that for HER-2/neu, E1A may inhibit the growth of tumors and help prevent metastasis. Studies also show that E1A can make cancer cells more sensitive to chemotherapy and radiation, and that the gene may induce immune system cells to attack cancer cells.

Phase II studies of tgDCC-E1A in patients with head and neck cancer have been conducted. In the phase II head and neck cancer study, a 7% complete response rate was observed, and nearly 50% of the patients had stable disease. A phase II study of tgDCC-E1A in combination with radiation therapy in patients with head and neck cancer has been initiated.

MULTIMEDIA

Section 7 of 8  

• Authors and Editors
• Introduction
• Epidermal Growth Factor Receptors
• Epidermal Growth Factor Receptor Inhibitors
• Summary
• Interleukin, Cyclooxygenase-2, Carcinoembryonic Antigen, and Targeted Genetics
• Multimedia
• References

Media file 1:  The epidermal growth factor receptor (HER) family consists of 4 closely related transmembrane receptors: HER-1/EGFR, HER-2, HER-3, and HER-4. Each receptor has an extracellular ligand-binding domain, a transmembrane region that anchors the receptor to the cell, and an intracellular cytoplasmic domain that contains a tyrosine kinase region and a carboxy terminal tail.
	View Full Size Image
Media type:  Image

Media file 2:  Normal cells and cancer cells rely on epidermal growth factor receptor (EGFR) signals, but the signal is not correctly regulated in cancer cells.
	View Full Size Image
Media type:  Image

REFERENCES

Section 8 of 8

• Authors and Editors
• Introduction
• Epidermal Growth Factor Receptors
• Epidermal Growth Factor Receptor Inhibitors
• Summary
• Interleukin, Cyclooxygenase-2, Carcinoembryonic Antigen, and Targeted Genetics
• Multimedia
• References

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Article Last Updated: Jan 8, 2008