The role of epidermal growth factor receptor in head and neck squamous cell carcinoma

Growth factor receptors play a crucial role in the cell proliferation pathways involved in the development of cancer. One such receptor, the epidermal growth factor receptor (EGFR), is upregulated in many types of human tumors, particularly head and neck squamous cell carcinoma (HNSCC). EGFR overexpression in HNSCC has been the basis for investigation of therapeutic strategies that target EGFR. EGFR-blocking methods under evaluation involve immunotoxins, monoclonal antibodies, EGFR-specific tyrosine kinase inhibitors, and antisense approaches. These molecular targeting tactics have produced a number of agents that are currently in various stages of preclinical investigation, along with clinical trials to assess their potential as anticancer treatments.     

Epidermal growth factor receptor pathway as therapeutic development in head and neck cancers: present and future

The understanding of the epidermal growth factor pathway in terms of intracellular signaling and its role in proliferation and cell survival has impacted the therapeutic management of many solid tumor malignancies in which this pathway has been dysregulated. Once the receptor is targeted at its cellular membrane level or tyrosine kinase domain, its blockage induces downregulation of oncogenic and tumorigenesis mechanisms which were in place, and thus inhibits proliferation and induces apoptosis of the malignant cell. Nowadays, we have several monoclonal antibodies as well as small molecules which target the receptor of epidermal growth factor. Although several receptors have been described within the human epidermal receptor family, our discussion will be focused on the impact of human epidermal receptor-1 as a therapeutic option for locally advanced squamous cell carcinoma of the head and neck.     

Novel therapeutics for head and neck cancer

Head and neck squamous cell carcinoma is a clinically challenging disease that resulted in more than 500,000 cases worldwide in 2001. In the United States, head and neck squamous cell carcinoma has accounted for approximately 40,000 cases with 12,000 deaths reported in 2001, which makes it the fifth leading cause of cancer incidence and the sixth leading cause of cancer-related deaths. Patients with recurrent or metastatic disease have a median survival rate of approximately 6 months; and there is little evidence from randomized trials that survival advantages have been achieved over the community standard of cisplatin and infusional 5-fluorouracil combination. Despite significant improvements in diagnosis, local management, and chemotherapy of head and neck cancer, there has been no significant increase in long-term survival rates over the past 30 years. As little progress has been made, new management approaches are required. Novel biologic agents have been developed to target multiple specific regions of the cancer cell. Epidermal growth factor receptor blockers have been investigated, such as anti epidermal growth factor receptor monoclonal antibodies, tyrosine kinase inhibitors, ligand conjugates, immunoconjugates, and antisense oligonucleotides. Farnesyl transferase inhibitors are a class of compounds that inhibit a critical enzymatic step in the constitutive expression of mutated ras genes, which are present in more than 27% of oral cancers. Strategies targeting the p53 gene and protein may halt or reverse the process of tumorigenesis and metastasis as p53 mutations occur in 45 to 70% of head and neck squamous cell carcinoma patients. Continued development of these novel agents may help improve the overall response and survival rate of patients with head and neck cancer.     

Targeting EGF-receptor-signalling in squamous cell carcinomas of the head and neck

Despite significant advances in the use of surgery, chemotherapy and radiotherapy to treat squamous cell carcinoma of the head and neck (SCCHN), prognosis has improved little over the past 30 years. There is a clear need for novel, more effective therapies to prevent relapse, control metastases and improve overall survival. Improved understanding of SCCHN disease biology has led to the introduction of molecularly targeted treatment strategies in these cancers. The epidermal growth factor receptor (EGFR) is expressed at much higher levels in SCCHN tumours than in normal epithelial tissue, and EGFR expression correlates with poor prognosis. Therefore, much effort is currently directed toward targeting aberrant EGFR activity (e.g. cell signalling) in SCCHN. This review discusses the efficacy of novel therapies targeting the EGFR (e.g. anti-EGFR antibodies and EGFR tyrosine kinase inhibitors) that are currently tested in SCCHN patients.     

Critical update and emerging trends in epidermal growth factor receptor targeting in cancer.

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase of the ErbB receptor family that is abnormally activated in many epithelial tumors. The aberrant activation of the EGFR leads to enhanced proliferation and other tumor-promoting activities, which provide a strong rationale to target this receptor family. There are two classes of anti-EGFR agents: monoclonal antibodies (MAbs) directed at the extracellular domain of the receptor and small molecule, adenosine triphosphate-competitive inhibitors of the receptor's tyrosine kinase. Anti-EGFR MAbs have shown antitumor activity in advanced colorectal carcinoma, squamous cell carcinomas of the head and neck, non-small-cell lung cancer (NSCLC) and renal cell carcinomas. The tyrosine kinase inhibitors (TKIs) have a partially different activity profile. They are active against NSCLC, and a specific EGFR inhibitor has shown improvement in survival. Recently, mutations and amplifications of the EGFR gene have been identified in NSCLC and predict for enhanced sensitivity to anti-EGFR TKIs. In addition to specific anti-EGFR TKIs, there are broader acting inhibitors such as dual EGFR HER-2 inhibitors and combined anti-pan-ErbB and antivascular endothelial growth factor receptor inhibitors. Current research efforts are directed at selecting the optimal dose and schedule and identifying predictive factors of response and resistance beyond EGFR gene mutations and/or amplifications. Finally, there is a need for improved strategies to integrate anti-EGFR agents with conventional therapies and to explore combinations with other molecular targeted approaches including other antireceptor therapies, receptor-downstream signaling transduction inhibitors, and targeted approaches interfering with other essential drivers of cancer, such as angiogenesis.     

Analysis of the epidermal growth factor receptor gene in fresh human head and neck tumors

Seventeen fresh uncultured tumors obtained from biopsies of patients with various forms of head and neck cancer and two squamous cell carcinoma cell lines were analyzed for RNA expression and structural alterations of the epidermal growth factor reception gene. We used cDNA probes for the external and the internal domains of the gene. Enhanced mRNA expression was found only in one squamous cell carcinoma cell line, which is known to have high levels of epidermal growth factor receptor. No amplification or structural rearrangement of the epidermal growth factor receptor gene was found.     

Enhancement of docetaxel-induced cytotoxicity by blocking epidermal growth factor receptor and cyclooxygenase-2 pathways in squamous cell carcinoma of the head and neck.

PURPOSE: The addition of molecular targeted agents to enhance the cytotoxicity of chemotherapeutic agents is a promising strategy in cancer treatment. The combination of cyclooxygenase-2 inhibitors and epidermal growth factor receptor tyrosine kinase inhibitors, such as celecoxib and ZD1839 (gefitinib), was reported to achieve synergistic cell growth inhibition in squamous cell carcinoma of the head and neck. Therefore, we postulated that the addition of celecoxib and ZD1839 to docetaxel, a cytotoxic agent, might further increase antitumor activity. EXPERIMENTAL DESIGN: The combination of celecoxib, ZD1839, and docetaxel was studied for its effect on cell growth and apoptosis by cell growth inhibition and Annexin V assays. The relevant molecular targets of these agents and apoptotic markers were examined by immunoblotting analyses in the presence or absence of these three drugs. Morphologic changes of the microtubule cytoskeleton, a known target of docetaxel, were also evaluated by staining for alpha-tubulin after the combination treatment. RESULTS: We showed that this triple combination significantly enhanced cell growth inhibition and docetaxel-induced apoptosis. Docetaxel mainly induced caspase-8 activation, whereas the addition of celecoxib and ZD1839 augmented the caspase-8 activation and enhanced caspase-9 activation. One of the underlying mechanisms for augmentation of docetaxel-induced apoptosis by celecoxib and ZD1839 is to further inhibit the activation of prosurvival pathway molecules, such as extracellular signal-regulated kinase and AKT, and the promotion of aberrant apoptosis. CONCLUSIONS: Our studies suggest that the combination of docetaxel with a cyclooxygenase-2 inhibitor and an epidermal growth factor receptor tyrosine kinase inhibitor may further improve efficacy of docetaxel and other taxane-based therapies in squamous cell carcinoma of the head and neck.     

EGFR antisense treatment of human HNSCC cell lines down-regulates VEGF expression and endothelial cell migration

Overexpression of the epidermal growth factor receptor (EGFR) is thought to play a key role in the development of head and neck squamous cell carcinoma (HNSCC) primarily through its effect on promoting uncontrolled cell proliferation. Blocking EGFR ligand binding might also inhibit angiogenesis and down-regulate the production of angiogenic factors. Angiogenesis is increased in various human tumors, including head and neck squamous cell carcinoma (HNSCC), and correlates with tumor progression and metastasis. The vascular endothelial growth factor (VEGF) is thought to be the most important angiogenic factor. We determined whether VEGF antisense oligonucleotide treatment can decrease angiogenic activity of HNSCC cell lines in vitro. By using a 21-mer antisense phosphorothioate oligonucleotide targeting the translation start site of human EGFR mRNA, we examined modulation of VEGF expression in cell line supernatants by capture ELISA, and in cell lysates by Western blotting. Human umbilica vein endothelial cells (HUVEC) were grown in conditioned medium produced from the treated tumor cells. Endothelial cell migration was measured using a modified Boyden chamber. EGFR antisense oligonucleotide treatment resulted in a significant reduction of VEGF protein expression compared to sense oligonucleotide control. Addition of conditioned medium from EGFR antisense-treated tumor cells resulted in decreased endothelial cell migration. In conclusion, therapeutic strategies targeting EGFR signaling in head and neck cancer might have an antitumor effect mediated in part by inhibition of tumor angiogenesis.     

Insulin-like growth factor receptor as a therapeutic target in head and neck cancer.

PURPOSE: Insulin-like growth factor type I receptor (IGF-IR) plays critical roles in epithelial cancer cell development, proliferation, motility, and survival, and new therapeutic agents targeting IGF-IR are in development. Another receptor tyrosine kinase, the epidermal growth factor receptor (EGFR), is an established therapeutic target in head and neck cancer and IGF-IR/EGFR heterodimerization has been reported in other epithelial cancers. The present study was undertaken to determine the effects of anti-IGF-IR therapeutic targeting on cell signaling and cancer cell phenotypes in squamous cell carcinomas of the head and neck (SCCHN). EXPERIMENTAL DESIGN: The therapeutic efficacy of the human anti-IGF-IR antibody IMC-A12 alone and in combination with the EGFR blocking antibody cetuximab (C225) was tested in SCCHN cell lines and in tumor xenografts. RESULTS: IGF-IR was overexpressed in human head and neck cancer cell lines and tumors. Pretreatment of serum-starved 183A or TU159 SCCHN cell lines with A12 (10 microg/mL) blocked IGF-stimulated activation of IGF-IR, insulin receptor substrate (IRS)-1 and IRS-2, mitogen-activated protein kinase, and phosphatidylinositol 3-kinase. A12 induced G(0)-G(1) cell cycle arrest and blocked cell growth, motility, and anchorage-independent growth. Stimulation of head and neck cancer cells with either IGF or EGF resulted in IGF-IR and EGFR heterodimerization, but only IGF caused activating phosphorylation of both receptors. Combined treatment with A12 and the EGFR blocking antibody C225 was more effective at reducing cell proliferation and migration than either agent alone. Finally, TU159 tongue cancer cell xenografts grown in athymic nude mice were treated thrice weekly for 4 weeks with vehicle, A12 (40 mg/kg i.p.), C225 (40 mg/kg i.p.), or both agents (n=8 mice per group; 2 tumors per mouse). Linear regression slope analysis showed significant differences in median tumor volume over time between all three treatment groups and the control group. Complete regression was seen in 31% (A12), 31% (C225), and 44% (A12 + C225) of tumors. CONCLUSION: Here we found the overexpression of IGF-IR, the functional heterodimerization of IGF-IR and EGFR, and effective therapeutic targeting of these receptors in human head and neck cancer xenografts.     

头颈部鳞癌分子靶向治疗进展

当前分子靶向治疗头颈部鳞状细胞癌(SCCHN)的进展非常快.由于表皮生长因子受体(EGFR)信号传导和血管发生在SCCHN的生长中起关键作用,因此EGFR及其下游效应器与血管发生过程相关的分子及其受体就成为目前SCCHN分子靶向治疗的主要靶点.     

The role of taxanes and targeted therapies in locally advanced head and neck cancer

PURPOSE OF REVIEW: This review presents new data on the role of taxanes and targeted therapies in the management of squamous cell carcinoma of the head and neck. RECENT FINDINGS: Taxane-containing triplets are clearly superior as an induction regimen in locally advanced squamous cell carcinoma of the head and neck when compared with cisplatin/5 fluorouracil which has been the standard for two decades. Preliminary data suggest that the addition of a taxane to cisplatin/5 fluorouracil as induction regimen followed by chemoradiation may be superior to chemoradiation alone. The addition of cetuximab to radiation prolongs locoregional control and survival without increasing mucositis. Areas of active investigation are the search for epidermal growth factor receptor mutations and the optimal way of integrating epidermal growth factor receptor-directed therapies into standard management. Meanwhile new targets are explored. SUMMARY: Taxane/cisplatin/5 fluorouracil induction chemotherapy is clearly superior to cisplatin/5 fluorouracil. Epidermal growth factor receptor directed therapies can safely be combined with radiation and the combination shows encouraging results.     

Targeted therapy for squamous cell carcinoma of the head and neck

Targeted agents have emerged as novel drugs in the oncology field based on our understanding of the biology of individual malignancies, and have had a promising impact in several tumors. Squamous cell carcinoma of the head and neck (SCCHN) is a common disease with little progress made in survival over the past few decades. SCCHN is characterized by overexpression of the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), both of which appear to have a prognostic value. Hence these receptors and their downstream pathways make attractive therapeutic targets. This review discusses targeted therapies currently being evaluated for their role in squamous cell carcinoma of the head and neck.     

The epidermal growth factor receptor as a target for colorectal cancer therapy

The epidermal growth factor receptor (EGFR) is the prototypical member of the erbB receptor family. The EGFR axis is activated by a variety of ligands that are crucial in the formation and propagation of many tumors, including colorectal cancer, through their effects on cell signaling pathways, cellular proliferation, control of apoptosis, and angiogenesis. The importance of the EGFR axis in tumorigenesis and tumor progression makes it an attractive target for the development of anticancer therapies. A variety of targeting strategies to exploit the role of EGFR in tumors have been employed. The most highly developed of these anti-EGFR approaches are the monoclonal antibodies and the tyrosine kinase inhibitors (TKIs). Clinical evaluations of these compounds have yielded some promising results. The role of the EGFR axis in colorectal cancer formation and progression is reviewed and the clinical development of these anticancer EGFR-targeted drugs is reviewed and updated.     

Targeted therapies in head and neck cancer

Over the past decade, the important role of different growth factors and their receptors and signal transduction pathways in the genesis and progression of tumors has been well recognized and their mechanism of action and interactions is gradually being unraveled. Epidermal growth factor receptor (EGFR) overexpression is present in the vast majority of squamous cell head and neck cancers and carries a worse prognosis. EGFR is the target of multiple specifically targeted monoclonal antibodies and tyrosine kinases, which are in various stages of clinical development in squamous cell carcinoma of the head and neck (SCCHN). The search for EGFR mutations is an area of active investigation. The incidence and impact of EGFR mutations in SCCHN has yet to be determined. EGFR downstream signaling pathways are the target of farnesyltransferase inhibitors (FTIs) and mammalian target of rapamycin (mTOR) inhibitors. Cyclooxygenase-2 (COX-2) is overexpressed in premalignant lesions (oral leukoplakia) and in squamous cell carcinoma of the head and neck. EGFR and COX-2 signaling pathways form a positive feedback loop. As their toxicity profiles are non-overlapping, combination of COX-2 inhibitors and EGFR targeted therapies looks attractive. The majority of the studies, although not all, examining the prognostic significance of vascular endothelial growth factor (VEGF) expressing did observe a worse outcome in patients with SCCHN expressing VEGF and VEGF receptor 2 (VEGFR-2). Anti-VEGF strategies include neutralizing antibodies to VEGF or VEGFR and VEGFR tyrosine kinase inhibitors. Aurora kinase inhibitors, insulin like growth factor inhibitors, and histone acetylase inhibitors have recently gained interest as potential new promising ways of tackling tumors including SCCHN.     

Expanding role of the medical oncologist in the management of head and neck cancer

The multidisciplinary approach to treating squamous cell carcinoma of the head and neck is complex and evolving. This article aims to review some recent developments in squamous cell carcinoma of the head and neck, in particular the expanding role of chemotherapy in its management. Surgery and radiotherapy have remained the mainstay of therapy. Chemotherapy is increasingly being incorporated into the treatment of squamous cell carcinoma of the head and neck. Previously, radiotherapy following surgery was the standard approach to the treatment of locoregionally advanced resectable disease. Data from randomized trials have confirmed the benefits of concurrent chemoradiotherapy in the adjuvant setting. Chemoradiotherapy is also the recommended approach for unresectable disease. Induction chemotherapy has been useful in resectable disease where organ preservation is desirable, but this approach was inferior for the goal of larynx preservation, while leading to similar survival when compared with concomitant chemoradiotherapy. There is recent evidence that taxanes added to induction chemotherapy with cisplatin and fluorouracil result in improved survival outcomes. Novel targeted agents, such as epidermal growth factor receptor antagonists, are showing promise in the treatment of patients with both locoregionally advanced and recurrent/metastatic squamous cell carcinoma of the head and neck.     

Balancing Safety and Efficacy of Epidermal Growth Factor Receptor Inhibitors in Patients With Squamous Cell Carcinoma of the Head and Neck

The epidermal growth factor receptor (EGFR) is overexpressed in more than 80% of squamous cell cancers of the head and neck (SCCHN). An evolving understanding of the role of EGFR in tumorigenesis has made the receptor an important therapeutic target in SCCHN. Several EGFR inhibitors (EGFRIs) are active in SCCHN, and their use is associated with improvement in progression-free survival and overall survival in various treatment settings. Nevertheless, EGFR inhibition is associated with significant mucocutaneous toxicity that must be balanced against its anticipated efficacy. This review summarizes the relevant clinical trial experience with EGFRIs, with attention to efficacy, toxicity, and methods of selecting patients most likely to benefit from therapy.

Implications for Practice:

Cetuximab and other inhibitors of the epidermal growth factor receptor (EGFR) have entered the medical oncologist’s arsenal against squamous cell carcinoma of the head and neck (SCCHN). They are modestly active as single agents and in combination with chemotherapy and radiotherapy. Despite their efficacy across multiple treatment settings, cetuximab and other EGFR inhibitors (EGFRIs) have not supplanted platinum-based therapies, which remain a standard of care for SCCHN. The modest benefits of EGFRI therapy must take into consideration patient, disease, and treatment characteristics and must be balanced against potential treatment toxicity.     

Enhanced antiangiogenic therapy of squamous cell carcinoma by combined endostatin and epidermal growth factor receptor-antisense therapy.

PURPOSE: We tested the combined effects of antiangiogenic endostatin and epidermal growth factor receptor (EGFR) antisense gene therapy on squamous cell carcinoma (SCC). EXPERIMENTAL DESIGN and Results: The 1483 cell line of human head and neck SCC (HNSCC) and SCC-VII/SF murine SCC cells was used to establish tumors in nude mice and immunocompetent C3H mice, respectively. Tumor-bearing mice were treated with endostatin (20 mg/kg/day, s.c.), liposomal EGFR-antisense expression plasmid (25 microg/mouse, three times/week, intratumoral), a combination of both agents, or liposomal EGFR-sense plasmid as a control. Endostatin or EGFR-antisense alone significantly, yet partially, inhibited the growth of 1483 and SCC-VII/SF tumors, and a combination of both treatments completely blocked tumor growth. Immunohistochemistry analysis demonstrated that a complete suppression of tumor angiogenesis was achieved by the combination treatment. Down-regulation of vascular endothelial growth factor was shown in EGFR-antisense-treated tumors. These results suggest that the EGFR-antisense treatment, in addition to its inhibitory activity on tumor cell proliferation, might have a synergistic effect with endostatin on SCC-induced angiogenesis. In vitro studies demonstrated that EGFR inhibition by antisense oligonucleotides or EGFR-specific tyrosine kinase inhibitor down-regulated the production of VEGF in HNSCC cells. Additional experiments demonstrated that these EGFR inhibition approaches also directly suppressed the growth of endothelial cells. CONCLUSION: A combination of endostatin and EGFR targeting strategies profoundly inhibited the angiogenesis and growth of SCC in vivo. EGFR-antisense therapy might have multiple inhibitory effects against both tumor cells and endothelial cells, leading to enhanced antitumor efficacy. Such a combination strategy might represent a novel and promising approach for HNSCC therapy.     

Combined inhibition of c-Src and epidermal growth factor receptor abrogates growth and invasion of head and neck squamous cell carcinoma

PURPOSE: Increased expression and/or activation of epidermal growth factor receptor (EGFR) is associated with tumor progression and poor prognosis in many cancers, including head and neck squamous cell carcinoma (HNSCC). Src family kinases, including c-Src, mediate a variety of intracellular or extracellular signals that contribute to tumor formation and progression. This study was undertaken to elucidate the role of c-Src in the growth and invasion of HNSCC and to determine the effects of combined targeting of EGFR and Src kinases in HNSCC cell lines. EXPERIMENTAL DESIGN: HNSCC cells were engineered to stably express a dominant-active form of c-Src and investigated in cell growth and invasion assays. The biochemical effects of combined treatment with the Src inhibitor AZD0530, a potent, orally active Src inhibitor with Bcr/Abl activity, and the EGFR kinase inhibitor gefitinib were examined, as well as the consequences of dual Src/EGFR targeting on the growth and invasion of a panel of HNSCC cell lines. RESULTS: HNSCC cells expressing dominant-active c-Src showed increased growth and invasion compared with vector-transfected controls. Combined treatment with AZD0530 and gefitinib resulted in greater inhibition of HNSCC cell growth and invasion compared with either agent alone. CONCLUSIONS: These results suggest that increased expression and activation of c-Src promotes HNSCC progression where combined targeting of EGFR and c-Src may be an efficacious treatment approach.     

Apoptosis and growth inhibition of head and neck tumor cell line induced by epidermal growth factor receptor tyrosine kinase inhibitor

Overexpression of the epidermal growth factor (EGF) receptor, a hallmark of aerodigestive squamous cell carcinoma of the head and neck (SCCHN), correlates with aggressive tumor behavior. There is evidence that SCCHN cells auto-activate their EGF receptors. The receptor has therefore attracted interest as a potential therapeutic target. We tested the in vitro therapeutic efficacy of PD153035--a potent, specific inhibitor of the tyrosine kinase intrinsic to the EGF receptor--by employing a well-characterized cell line derived from human gingival SCCHN. DNA-synthesis and cell number were assayed for growth-inhibitory effects, phosphorylation of the EGF receptor was quantitated by immunoblot, and cell apoptosis was detected by terminal deoxytransferase (TdT)-mediated deoxyuridine triphosphate (dUTP)-biotin nick end labeling (TUNEL) in situ assay. PD153035, at nanomolar concentrations, inhibited autophosphorylation of the EGF receptor induced by EGF stimulation and the inhibition occurred in a dose-dependent manner. Under the same conditions, PD153035 inhibited cell growth, and induced apoptosis of SCCHN cells in vitro. We conclude that selective inhibition of the EGF receptor tyrosine kinase completely abolishes EGF receptor phosphorylation resulting from receptor stimulation, and results in growth inhibition and apoptosis of SCCHN cells in vitro. By inducing cytostasis and apoptosis, this new class of inhibitors may be of therapeutic value against SCCHN.     

Monoclonal antibodies as potentiators of radiotherapy and chemotherapy in the management of head and neck cancer.

The overall survival of patients with squamous cell cancer of the head and neck has not significantly improved over the past 2 decades. Preclinical studies suggest that combining a monoclonal antibody to the epidermal growth factor receptor with irradiation or chemotherapy agents active in squamous cell cancer of the head and neck could increase treatment efficacy. Completed phase I studies have shown these combinations to be both feasible and tolerable. Phase III studies are now beginning to establish firmly the efficacy of this innovative new approach.