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Year : 2010  |  Volume : 47  |  Issue : 3  |  Page : 248--259

Novel therapeutic approaches to squamous cell carcinoma of the head and neck using biologically targeted agents

KJ Harrington1, R Kazi2, SA Bhide1, K Newbold2, CM Nutting1,  
1 Head and Neck Unit, The Royal Marsden Hospital, London and Surrey; The Institute of Cancer Research, 237 Fulham Road, London, United Kingdom
2 Head and Neck Unit, The Royal Marsden Hospital, London and Surrey, United Kingdom

Correspondence Address:
K J Harrington
Head and Neck Unit, The Royal Marsden Hospital, London and Surrey; The Institute of Cancer Research, 237 Fulham Road, London
United Kingdom


Despite significant improvements in the treatment and outcomes of patients with squamous cell carcinoma of the head and neck (SCCHN) that have resulted from technological advances in radiation delivery and the use of cytotoxic chemotherapy, there is still a pressing need for novel therapies. In the last two decades, our understanding of the molecular biological basis of cancer has provided us with a new framework for developing specific targeted therapies. It is likely that the next wave of developments will include active small molecule inhibitors of epidermal growth factor receptor (EGFR) (and other members of the c-erbB family of receptors), antiangiogenic agents, and drugs that can increase proapoptotic signaling in cancer cells. As with cetuximab, it is most likely that these new agents will first find a niche in the context of combination regimens with standard anticancer therapeutics.

How to cite this article:
Harrington K J, Kazi R, Bhide S A, Newbold K, Nutting C M. Novel therapeutic approaches to squamous cell carcinoma of the head and neck using biologically targeted agents.Indian J Cancer 2010;47:248-259

How to cite this URL:
Harrington K J, Kazi R, Bhide S A, Newbold K, Nutting C M. Novel therapeutic approaches to squamous cell carcinoma of the head and neck using biologically targeted agents. Indian J Cancer [serial online] 2010 [cited 2019 Aug 20 ];47:248-259
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The nonsurgical management of squamous cell carcinoma of the head and neck (SCCHN) has undergone significant changes in the last decade. These include the following: (1) technologic advances in radiation delivery as a means of reducing normal tissue toxicity and increasing dose to tumor tissue; [1],[2],[3],[4],[5] (2) demonstration of the superiority of concomitant chemoradiotherapy over radiotherapy alone in definitive [6] and adjuvant settings; [7],[8] and (3) identification of molecular biological processes that drive the disease and the development of new therapies that specifically target them. [9]

Understanding the molecular biology of cancer has fundamentally changed the search for new therapies for malignant disease. Central to this shift has been the realization that cancer is a genetic disease that occurs when the information contained in cellular DNA is corrupted or decoded aberrantly. These changes manifest as altered patterns of gene expression, which are detected in cancer cells in terms of derangement of normal protein function. In simple terms, the genetic changes that result in the development of cancers mediate 2 general effects: (1) enhancement of the activity of genes that stimulate cell growth, survival, and spread; and (2) reduction of the actions of genes that repress these processes. As a result, cancer cells acquire properties that allow them to grow in an uncontrolled fashion, invade adjacent normal tissues, recruit a dedicated blood supply, spread to distant sites, and develop resistance to anticancer treatments.

In this review, we describe the key cellular processes that are altered in SCCHN cells as a basis for discussing the new therapeutic opportunities that exist in the treatment of SCCHN.

 The Molecular Biology of SCCHN

Cancer genes

The functions of 2 classes of genes (oncogenes and tumor suppressor genes) lie at the heart of any understanding of the biology of cancer as reviewed. [10]

Oncogenes are derived from mutated versions of normal cellular genes (called proto-oncogenes) that encode proteins that control cell proliferation, survival, and spread. In normal cells, the expression of proto-oncogenes is tightly regulated to avoid uncontrolled cell growth. In cancer, abnormalities of proto-oncogenes cause uncontrolled cell division, enhanced survival (even during anticancer treatment), and dissemination. Oncogenes are phenotypically dominant, that is, a single mutated copy of a proto-oncogene can promote cancer, and are never responsible for inherited cancer syndromes. Oncogenes can be activated in 3 ways to cause cancers: (1) gene mutation involves the acquisition of a specific defect in the genetic sequence such that the gene has enhanced function; (2) gene amplification occurs when a gene retains its normal sequence, but the gene multiplies repeatedly in the chromosome; (3) gene translocation involves the gene being moved from its normal chromosomal position (locus) to a new position (usually on a different chromosome) where it comes under the influence of a new, more active promoter element.

Tumor suppressor genes (TSG) are normal cellular genes whose function inhibits cell proliferation and survival. They frequently control cell cycle progression and apoptosis. TSG are phenotypically recessive, that is, the function of both copies must be lost to promote cancer, and are responsible for inherited cancer syndromes. In familial cancer syndromes, individuals inherit a germline mutation in one copy (allele) of a TSG such that every cell in the body is affected. It is, therefore, highly likely that at least one cell in the body will suffer complete loss of TSG function because only one copy has to be mutated (so-called loss of heterozygosity). As a result, hereditary cancer syndromes often give rise to multiple cancers at an early age.

The hallmarks of cancer

Hanahan and Weinberg (2000) [11] described 6 key changes that occur in cancers, which are largely responsible for driving their malignant behavior [Table 1]. This schema provides a useful way of thinking about the different ways of targeting tumors. For individual tumor types, it is clear that some processes represent better targets than others. In the following sections, the individual hallmarks of cancer are discussed and their potential as targets for therapeutic intervention in SCCHN has been reviewed.

Targeting growth factor independence

A simplified scheme for the function of growth factor receptors (GFRs) and their ligands in promoting SCCHN cell growth (and other effects) is shown in [Figure 1]. The binding of the cognate ligand to the specific ligand-binding domain on the extracellular component of the GFR leads to a change in the shape of the protein that allows it to form a dimer (2 protein molecules) with an identical GFR (homodimer) or with other members of the same receptor family (heterodimer). This dimerization process results in the intracytoplasmic domains of the adjacent receptors adding phosphate groups to tyrosine residues on the other. For this reason, these receptors are known as tyrosine kinase (TK) receptors. Phosphorylation of tyrosine residues in the tails of the receptors leads to a cascade of signals via the so-called secondary messengers such that the binding of a protein on the cell surface is able to influence the cell's behavior. Under normal circumstances, activation of GFRs is tightly controlled, as is the synthesis and release of the ligands that bind to them. The signaling pathway is normally responsible for regulating physiologic cellular processes, such as epithelial tissue development and response to injury.

c-erbB receptor family

One extremely important family of GFR is represented by the c-erbB receptors of the transmembrane type I receptor TK family. This family comprises 4 members: the epidermal GFR (EGFR) or c-erbB-1, c-erbB-2/neu/HER-2, c-erbB-3/HER-3, and c-erbB-4/HER-4. [12],[13] They consist of a glycosylated extracellular ligand-binding domain, a hydrophobic transmembrane component, and an intracellular domain with TK activity.

SCCHN very frequently (>90%) subverts normal EGFR-mediated signaling pathways, [12] and thus gains a growth and survival advantage over neighboring normal cells. Cancer cells exploit 3 main strategies for achieving self-sufficiency in growth factors: (1) they manufacture and release growth factors, which stimulate their own receptors (autocrine signaling) and those of their immediate neighbors (paracrine signaling); (2) they alter the number, structure, or function of their surface GFRs so that they are more likely to relay a growth signal to the nucleus (even in the absence of cognate ligand); and (3) they deregulate the signaling pathway downstream of the GFR so that it is permanently turned on (constitutively active).

SCCHN is probably the most clearly described example of EGFR-driven oncogenesis because this is the dominant signaling pathway responsible for the malignant features of the disease, and overexpression has been shown to correlate with poor survival. [14],[15] Currently, 12 major ligands with a shared EGF-like motif and affinity for the family of c-erbB receptors are known. The consequences of receptor dimerization and activation and subsequent intracellular signaling provide mechanistic explanations for many of the features that characterize SCCHN. [16] EGFR is a 170-kDa protein and the founding member of the receptor family. [17] In contrast to certain tumor types where EGFR gene amplification or mutation is implicated, overexpression of the receptor, without gene amplification, appears to be the dominant process in SCCHN. Elevated levels of EGFR mRNA and protein and of the ligand-transforming growth factor-alpha (TGF-α) are present in normal mucosa several centimeters from a malignant lesion. TGF-a upregulation is also detectable in preinvasive lesions and mild dysplasia, consistent with the theory of "field cancerization" due to exposure to environmental chemical carcinogens. [18],[19],[20] Upregulation of EGFR is a significant early event in the progression from preinvasive mucosal dysplasia to invasive SCCHN and is most marked in more dysplastic lesions. [20]

Several studies have shown links between EGFR overexpression and SCCHN oncogenesis and progression.[21],[22],[23] In an experimental xenograft model where highly metastatic sublines were isolated by in vivo selection from nodal metastases, EGFR was one of only 33 differentially expressed genes, showing a 2-fold upregulation. [24] A mutated version of EGFR (EGFRvIII) is the most common of 7 known variants of EGFR. Deletion of exons 2-7 of the EGFR gene results in a truncated extracellular domain and constitutive activation of the intracellular TK, which continuously triggers multiple downstream phosphorylation cascades. EGFRvIII can associate with and activate wild-type EGFR in the absence of a ligand. This particular mutation is common in tumor types, such as glioblastoma multiforme and non-small cell lung cancer, and has recently been reported to be present in 42% of head and neck cancers. [25]

The c-erbB-2 receptor is a 185-kDa receptor-like phosphoglycoprotein with no known exogenous ligand. When highly overexpressed, it may spontaneously dimerize and autoactivate, but it is more frequently activated by heterodimerization with other erbB receptors. The contribution of c-erbB-2 expression to the pathogenesis of SCCHN is not clearly defined. However, c-erbB-2:c-erbB-3 heterodimers are potent inducers of the PI3-kinase antiapoptotic pathway [26] as c-erbB-3 can bind directly to the PI3-kinase p85 subunit. Increasing expression of c-erbB-2 has been shown in parallel with the acquisition of a more malignant phenotype in oral carcinomas, which may imply a role in progression. [23],[27] The distribution of c-erbB-3 protein in tissues is different from that of EGFR and c-erbB-2. It does not have intrinsic TK activity, but it can be transphosphorylated by both EGFR and c-erbB2. Its overexpression (but not amplification) has been found in SCCHN cell lines, and in some cases it has been related to malignant potential. There has been comparatively little investigation of erbB-3 and erbB-4 in clinical samples from SCCHN, probably due to the low detection (~10%) in immunohistochemical surveys of clinical specimens. [28] Xia et al have indicated that the expression of all 4 receptors is associated with shortened survival in patients with oral SCC, with the combination of EGFR, erbB- 2, and erbB-3 (but not erbB-4) giving the greatest prognostic information. [29]

c-erbB receptor family as a therapeutic target

c-erbB receptors are extremely attractive molecular targets in SCCHN, because their overexpression in tumor cells offers a level of antitumor selectivity [Figure 1]. Two classes of drugs have entered clinical trials: (1) monoclonal antibodies (MAB) directed against the extracellular domain of the receptor; and (2) small molecules inhibiting receptor TK activity (-tyrosine kinase inhibitors [TKi]). The relative advantages and disadvantages of EGFR blocking agents are detailed in [Table 2].

Anti-EGFR monoclonal antibodies

A number of MAB have been developed for clinical evaluation. They differ from one another in terms of their species of origin (murine, chimeric, or fully humanized) and the specific part (epitope) of the target protein that they recognize. Cetuximab (C225, Erbitux) is a human-murine chimeric monoclonal antibody against EGFR, which has undergone extensive preclinical and clinical evaluations. In vitro studies have shown its antitumor activity against tumor cell lines through a range of mechanisms, including an antiproliferative effect, direct cytotoxicity, and the potentiation of the cytotoxic effects of chemotherapy or radiotherapy. [30],[31],[32],[33] In addition, in vivo experiments have demonstrated antiangiogenic effects. [34] This agent has been evaluated in early-stage clinical trials with favorable indications of efficacy in combination with chemotherapy or radiotherapy. [35],[36],[37],[38],[39]

The most significant trial to date reporting on the impact of EGFR inhibition in combination with radiotherapy was conducted using cetuximab in 424 patients with locally advanced SCCHN. [40] The patients were randomly allocated to treatment with either radical radiotherapy alone or in combination with weekly cetuximab. The combination treatment arm had significantly improved locoregional control (24.4 vs 14.9 months, P = 0.005), improved progression-free survival (P = 0.006), and improved overall survival (P = 0.03). Cetuximab was associated with a higher incidence of rash and infusion reactions, but otherwise the grade 3 and greater toxic effects were the same in the 2 groups. Further studies are in progress addressing the use of cetuximab in combination with radical chemoradiotherapy in patients with locally advanced SCCHN.

Cetuximab has also recently been shown to improve the outcome of palliative chemotherapy in a large randomized phase III study. [41] This is the first new agent to demonstrate an improvement in survival in the setting of relapsed/metastatic SCCHN. In this study in 442 eligible patients with untreated recurrent or metastatic SCCHN, cisplatin (100 mg/m 2 ) or carboplatin (area under the curve of 5 mg/mL/min) plus 5-fluorouracil (1 g/m 2 per day for 4 days) was given every 3 weeks for a maximum of 6 cycles. Two hundred and twenty-two patients received the same chemotherapy plus cetuximab (400 mg/m 2 initially, then 250 mg/m 2 per week) for a maximum of 6 cycles. Patients with stable disease who received chemotherapy plus cetuximab continued with cetuximab until disease progression or unacceptable toxicity. Adding cetuximab to platinum-based chemotherapy with fluorouracil prolonged median overall survival from 7.4 to 10.1 months (P = 0.04). The median progression-free survival time was prolonged from 3.3 to 5.6 months (P P [42],[43],[44] These agents differ from cetuximab, which is a chimeric human/murine antibody, in terms of their degree of humanization. Randomized evaluations of these agents in settings that are similar to those in which cetuximab has proven activity are ongoing and are likely to yield interesting and important data in the near future.

Small molecule tyrosine kinase inhibitors

Gefitinib (ZD1839, Iressa) is a low-molecular weight TKi that is highly specific for EGFR. By competing with adenosine triphosphate on the intracellular domain of EGFR it has been shown to prevent receptor autophosphorylation, with resultant antiproliferative effects observed in a variety of human xenograft models. Furthermore, combining gefitinib with cytotoxic chemotherapy increases growth inhibition and apoptotic cell death. [45],[46],[47]

Gefitinib was evaluated in phase I trials that included 28 patients with head and neck cancer. [48],[49],[50],[51] It was well tolerated at doses from 150 to 800 mg/m 2 , the most frequent grade 1 or 2 toxicities were diarrhea (47-55%), asthenia (44%), and an acneiform follicular rash (46-64%). Antitumor activity, including both partial responses and cases of prolonged stable disease, was observed at all doses. Clinically meaningful stable disease was achieved in 50% of patients with SCCHN, and quality-of-life ratings also remained stable during treatment, except in one study where they improved significantly over time. [52]

A phase II study has evaluated oral gefitinib (500 mg/day) as first or second-line monotherapy in 52 patients with recurrent or metastatic SCCHN most of whom had previously received combination chemotherapy or radiotherapy. [53],[54] Forty-seven patients were evaluable for tumor response and an objective partial response rate of 10.6% (one complete response) was demonstrated. Disease control, defined as objective tumor response plus stable disease, was achieved in 53% of patients and was sustained for more than 6 months in 13% of patients. The response rates and survival times of patients who received gefitinib as first-line therapy were not significantly different to those of patients who had received prior chemotherapy. Overall, the median times to progression and death were 3.4 months and 8.1 months, respectively, with an estimated 1-year survival of 29%. These results are more favorable than those achieved with chemotherapy in this setting, but with the additional benefit of reduced treatment-related toxicity. There was only a single case of grade 4 toxicity (hypercalcemia), a 4-6% incidence of grade 3 toxicity (anorexia, diarrhea, nausea, and hypercalcemia), grade 1 or 2 skin rash in 48%, and grade 1 or 2 diarrhea in 50%. A second study using single-agent gefitinib at a dose of 500 mg/day has also been reported. [55] Clinical, symptomatic, and radiologic response, time to progression, survival, and toxicity were recorded. Forty-seven patients were treated and the observed clinical response rate was 8% with a disease control rate (complete response, partial response, stable disease) of 36%. Thirty-four percent of patients experienced a symptomatic improvement. The median time to progression and survival were 2.6 and 4.3 months, respectively. Acneiform folliculitis was the most frequent toxicity observed (76%), but the majority of cases were grade 1 or 2. Only 4 patients experienced grade 3 toxicity of any type (all cases of folliculitis).

Lapatinib is an oral dual TKi with action against both EGFR (c-erbB1, HER-1) and c-erbB2 (HER-2). [56],[57] It has demonstrated activity both in vitro and in vivo, as well as showing tolerability in phase I clinical trials. [57] A placebo-controlled randomized phase 0 biomarker study has been performed with this agent in patients with advanced SCCHN. A single-agent response rate of 17% was reported, with biomarker evidence of significantly reduced proliferation and receptor phosphorylation in the lapatinib-treated group. [58] A phase I dose escalation study of lapatinib administered during radical chemoradiotherapy has been completed in patients with stage III and IV head and neck cancer. [59] Patients were enrolled in 3 cohorts of escalating lapatinib dose: 500, 1000, and 1500 mg/day. The patients received lapatinib alone for 1 week followed by 6.5-7 weeks of the same dose of lapatinib plus radiotherapy 66-70 Gy and cisplatin 100 mg/m 2 on Days 1, 22, and 43 of radiotherapy. Endpoints included safety/tolerability and clinical activity. Thirty-one patients were enrolled (7 in each of the 500 and 1000 mg cohorts, 17 in the 1500 mg cohort [14 in a safety cohort]). Dose-limiting toxicities (DLT) observed were perforated ulcer in 1 patient in the 500 mg cohort, and transient elevation of liver enzymes in 1 patient in the 1000 mg cohort. No DLTs were observed in the 1500 mg cohort. The recommended phase II dose was therefore defined as lapatinib 1500 mg/day with chemoradiation. The most common grade 3-4 adverse events were radiation mucositis, radiation dermatitis, lymphopenia, and neutropenia. No patients experienced drug-related symptomatic cardiotoxicity, and no interstitial pneumonitis was reported. The overall response rate was 81% (65% at the recommended phase II dose). The recommended phase II dose is lapatinib 1500 mg/day with chemoradiation in patients with locally advanced SCCHN, and is associated with an acceptable tolerability profile. Based on these findings, randomized phase II and III studies of lapatinib plus chemoradiation have been initiated. The results of these studies are awaited with interest.

 Targeting Sustained Angiogenesis

In normal tissues, the growth of new blood vessels (angiogenesis) is held very tightly in check by a balance between positive (proangiogenic-eg, vascular endothelial growth factor [VEGF]) and negative (antiangiogenic-eg, angiostatin) signals. The growth of cancer deposits is related to their ability to secure a blood supply. A small cluster of cancer cells can grow to 60-100 μm by deriving a supply of oxygen and nutrients by direct diffusion, but beyond this size the nascent tumor must acquire its own blood supply. Cancers acquire their new blood supply by subverting the balance between pro- and antiangiogenic factors. [60],[61] Essentially, cancers switch to an "angiogenic phenotype" by upregulating production of proangiogenic proteins, such as VEGF, basic fibroblast growth factor (βFGF), and platelet-derived growth factor (PDGF) and/or by downregulating the production of antiangiogenic proteins, such as thrombospondin-1, angiostatin, and endostatin. Cancer-associated endothelial cells have receptors for both growth promoting and inhibitory factors [Figure 2]. The binding of cognate ligand to a VEGF receptor on the endothelial cell causes receptor TK activation and downstream signaling to stimulate endothelial cell proliferation, vessel permeability, and migration. The net result is the formation of new blood vessels. VEGF production in tumor cells is frequently under the control of hypoxia inducible factor-1α, which is a transcription factor that is activated by low cellular oxygen tension.

Drugs that target angiogenesis are classified into 2 main groups: (1) vascular disrupting agents; and (2) antiangiogenic agents. [62] Vascular disrupting agents cause rapid and selective damage to existing tumor vasculature leading to tumor death. Tubulin-destabilizing agents, such as combretastatin A4 phosphate and ZD6126, are 2 such agents. [62],[63],[64] The attraction of these drugs is their potential ability to deprive large areas of tumor of a blood supply, with resulting widespread tumor cell death. As such, they are likely to lead to tumor regressions. However, their ability to cause vascular shutdown may also theoretically increase the presence of tumor hypoxia-a factor that is known to be correlated with resistance to standard therapeutics. Antiangiogenic agents work in a completely different fashion by inhibiting new blood vessel formation, without having an effect on established tumor vasculature. This is achieved by either binding VEGF or inhibiting VEGF-R activation. [61] Bevacizumab (Avastin) is a humanized monoclonal antibody to the VEGFR ligand VEGF-A. VEGF-R TKis also have antiangiogenic properties through their ability to inhibit phosphorylation of the tyrosine residues in the cytoplasmic domain of the receptor. A number of small molecule TKis (SU6668, SU5416 (semaxanib), SU11248 (sunitinib), SU11657, PTK787/ZK222584 (vatalanib), and ZD6474) have shown promise in tumor types other than SCCHN. [61] It is highly likely that these agents will be assessed in SCCHN in combination with chemotherapy and/or radiotherapy.

As regards the combination of vascular disrupting or antiangiogenic agents with standard therapeutic agents (radiotherapy, chemotherapy), there are a number of theoretic considerations that might suggest that this approach could be detrimental. For example, depriving a tumor of its blood supply (either acutely by vascular disruption or chronically by reducing angiogenesis) is likely to increase tumor hypoxia-a factor that is known to mediate treatment resistance. However, for the antiangiogenic agents, Jain and colleagues have suggested that treatment can lead to normalization of the tumor vasculature-if the dose and duration of treatment lie within certain parameters. [65],[66] The existence of this so-called vascular normalization window is supported by experimental data, but not yet by clinical trial findings. In addition, for the vascular disrupting drugs, it is possible that they can be used to trap radiosensitizing compounds or cytotoxic drugs within the tumor tissue by collapsing the vascular networks that will serve to wash the drug out of the tissue. In view of both these rationalizations, there is enormous interest in combining anti-VEGF MAB, VEGF-R TKis, and vascular disrupting agents with radiation and/or chemotherapy.

 Targeting Apoptosis

Normal cells continually audit their viability by measuring the balance of incoming survival (antiapoptotic) and death (proapoptotic) signals. In normal cells, DNA damage causes a block in proliferation (cell cycle arrest), while the potential for repair is assessed. If the level of damage exceeds the repair capacity, the balance of anti- and proapoptotic signals tips and the cell undergoes programmed cell death (apoptosis). This prevents maintenance of DNA damage and avoids the risk that mutations will be passed to the progeny of cell division. As such, this mechanism represents a very powerful barrier to the development of cancer.

Loss of normal apoptotic pathway signaling is a common event in cancer. Indeed, 2 of the best known cancer-associated genes (p53 [TSG] and bcl-2 [oncogene]) are intimately involved in apoptosis. The 2 main mechanisms of apoptotic signaling (intrinsic and extrinsic pathways) are illustrated in a simplified form in [Figure 3]. Cancer cells are able to evade apoptosis through an ability to ignore signals sent through the extrinsic pathway or by re-setting the balance of intracellular pro- and antiapoptotic molecules in favor of inhibition of apoptosis. By circumventing apoptosis, cancer cells can sustain DNA damage without it causing cell death (unless the damage is to a gene that is absolutely necessary for cell survival). Therefore, cancer cells that have switched off their apoptotic pathway are more likely to be intrinsically resistant to anticancer treatments. In fact, the use of these treatments may promote the accumulation of other mutations that may have a negative influence on the biology of the disease.

Therefore, targeting the apoptotic machinery represents a potentially attractive new therapeutic option in a range of cancers, including SCCHN. In general terms, there are 2 specific strategies that are under investigation: enhancing proapoptotic signaling by stimulating the extrinsic pathway and blocking the antiapoptotic regulators of the intrinsic pathway [Figure 3].

The first of these approaches has been assessed preclinically and in early-phase clinical trials, using both recombinant proapoptotic receptor ligands (recombinant human apoptotic ligand 2/tumor necrosis factor-related apoptosis, inducing ligand [rhApo2L/TRAIL]) [67] and MAB that can stimulate the DR4 and DR5 death receptors. [68] Agonistic humanized or human MAB against DR4 and DR5 have been tested in phase I and II trials in patients with advanced cancer (other than SCCHN). [68] These trials have shown that these antibodies are well tolerated and are capable of producing prolonged stable disease. Clinical studies in which TRAIL-receptor antibodies are being investigated in combination treatment regimens in patients with advanced cancer are ongoing. It is anticipated that the results from a broad spectrum of cancer therapy clinical trials will identify the activity and toxicity profiles of TRAIL death receptor antibodies as single agents, or in combination with chemotherapy agents or radiotherapy. Studies in patients with head and neck cancer are ongoing and will be reported in the near future.

The second approach to enhancing apoptosis is targeted blockade of antiapoptotic signaling pathways. This strategy has largely relied on using antisense oligonucleotides to reduce the expression of proteins, such as Bcl-2, in cancer cells. In vitro and in vivo studies in murine models have suggested that targeted reduction of Bcl-2 expression can enhance the therapeutic efficacy of chemotherapy or radiotherapy in head and neck models. [69],[70] However, this has not yet been tested in patients with SCCHN. In recent years, another means of blocking antiapoptotic regulators of the intrinsic pathway has received considerable research attention. This approach is based on blocking the actions of apoptosis proteins (IAP) inhibitor. [71] A prime example of this group of proteins is provided by the X-linked inhibitor of apoptosis protein (XIAP), which is a component of the final common pathway that inhibits caspases and suppresses apoptosis. XIAP is overexpressed in many cancer cell lines and cancer tissues and its expression has been correlated with resistance to chemotherapy and radiotherapy and to poor clinical outcome. The inhibition of XIAP can be achieved with either antisense oligonucleotides or small molecule inhibitors. In vitro, XIAP antagonists produce XIAP knockdown and apoptosis, which is associated with sensitization of tumor cells to radiotherapy and cytotoxic drugs. [71] In vivo, XIAP antagonists have antitumor effects and sensitize tumors to the effects of chemotherapy. This group of agents is currently undergoing phase I evaluation and may have potential in solid cancers, such as SCCHN.

 Targeting Insensitivity to Antigrowth Signals

There are a number of normal antigrowth signals that counteract the positively acting growth signals described above. Antigrowth signals work either by forcing cells into quiescence (G0 stage of the cell cycle) or by inducing their terminal differentiation such that they are permanently unable to re-enter the cell cycle. Antigrowth signaling is mediated by ligands (eg, transforming growth factor-beta, TGF-b) that act on cellular receptors (e.g. TGF-b receptor) and send signals to the nucleus via second messengers. These pathways are mainly involved in controlling the cell cycle clock and mediate their effects through proteins that include retinoblastoma protein (Rb), cyclins, cyclin-dependent kinases (CDK), and their inhibitors (CDKi). Abnormalities in antigrowth signaling pathways are extremely common in cancer and play a role in helping cancer cells to progress through the cell cycle. Therefore, loss of Rb and members of the CDKi family and overexpression of certain cyclins and CDK have been shown to occur in a large number of tumor types.

Clinical attempts to target the proliferation through cell cycle control are in their very early stages. The cyclin-dependent kinase inhibitor, Seliciclib (CYC202; R-roscovitine), has been shown to enhance apoptosis in head and neck cancer cells in preclinical studies. [72] It is the first selective, orally bioavailable inhibitor of cyclin-dependent kinases 1, 2, 7, and 9 to enter the clinic. In a phase I trial in 21 patients at doses of 100, 200, and 800 mg twice daily, it caused dose-limiting toxicities at the 800 mg dose. [73] No objective tumor responses were noted, but disease stabilization was recorded in 8 patients. Other similar agents are in development and will enter clinical trials in patients with a range of malignancies, including head and neck cancer, in the coming years.

 Targeting Cellular Immortalization

Normal somatic cells can only undergo a finite number of cell divisions (Hayflick limit) before they enter a period of permanent growth arrest known as replicative senescence. This process occurs as a result of the cells' inability to replicate the ends of their chromosomes (the telomeres) fully at each division. Therefore, over time the telomeres get progressively shorter, effectively acting as molecular clocks that count down the cells' lifespan. In contrast, stem cells and malignant cells have acquired immortality by maintaining the length of their telomeres. In most tumors, this occurs through upregulation of the enzyme telomerase, but in 10-15% of cases a different mechanism called alternative lengthening of the telomeres is responsible. Telomerase enzymatic activity involves a large number of proteins, but its 2 main components are an RNA template (hTR) and a reverse transcriptase enzyme (hTERT): The reverse transcriptase uses the hTR RNA template as a guide in the resynthesis of the DNA sequence of the telomere. Therefore, tumors that have reactivated the expression of telomerase are able to rebuild the parts of their telomeres that they lose with each round of cell division and, so, are able to avoid being sidelined into replicative senescence.

At present, efforts to target the immortalized, stem cell compartment within tumors remains in its infancy. Nonetheless, recognition of the importance of these cells to the overall behavior of the tumor, in terms of its ability to self-propagate, spread, and resist therapeutic intervention, means that active efforts will be made to devise specific targeted therapies against this compartment. Such developments are likely to result in novel approaches to the treatment of a range of tumor types, including SCCHN.

 Targeting Invasion and Metastasis

Distant metastases cause 90% of cancer deaths. Invasion and metastasis involves careful orchestration of a series of complex biological processes: (1) detachment from immediate neighbors and stroma at the local site; (2) enzymatic digestion of the extracellular matrix followed by specific directional motility; (3) penetration (intravasation) of blood or lymphatic vessels and tumor embolization; (4) survival in the circulation until arrival at the metastatic site that may be chosen on the basis of provision of a favorable supply of appropriate growth factors; (5) it adheres to the endothelium of blood vessels at its destination and extravasates from the vessel; and (6) it begins to proliferate and invade its new location and sets about recruiting a new blood supply.

The development of metastatic disease in locoregional cervical lymph nodes is a hallmark of SCCHN. Such is the predilection of this disease for lymphatic metastasis that patients may present with pathologically involved cervical nodes at any time during the natural history of the disease. [74] The phenomenon of cervical nodal metastasis from an occult primary mucosal site in the head and neck is also well recognized. [75] In addition, involved cervical nodes can present synchronously with the primary tumor or metachronously as the first sign of disease relapse. The presence or absence of lymphatic metastasis is the most important prognostic factor for patients with SCCHN. [76] On the basis of this fact, most patients who are diagnosed as having SCCHN will have radiologic investigations, such as computed tomography or magnetic resonance imaging in an attempt to identify nodal metastases. Even if these tests suggest that the neck is not involved (clinically node negative or cN0 disease), patients frequently undergo prophylactic treatment of the neck, either by elective neck dissection or radiotherapy, in an attempt to ablate occult micrometastases. Such additional treatment carries a significant morbidity for the patient. For those patients who present with N+ disease, there is a greater risk of systemic metastasis, which increases with increasing N stage and involvement of nodes lower in the neck (eg, level IV compared with level I). The identification of a panel of biomarkers that could predict the likelihood of nodal metastases would represent a useful tool for patient selection for elective or adjuvant treatment of the neck. Alternatively, novel therapies that could reduce the risk of local or systemic metastasis would represent a very significant advancement in the treatment of SCCHN.

There is evolving evidence that the patterns of metastasis of different cancers to specific organs (eg, SCCHN to cervical lymph nodes; breast cancer to liver, bone and brain; lung cancer to brain and adrenal gland) are not random, but appear to be driven by the expression of chemokine receptors by tumor cells that allow them to "seek" a suitable environment in which to establish a colony. Chemokines are small, secreted proteins with characteristic cysteine motifs in their amino acid sequences. [77] Most members of the chemokine superfamily have 4 cysteines and on this basis, they have been classified into 4 groups (CXC, CC, C or and CXC3 ) according to the motif displayed by the first 2 cysteines. Chemokines interact with their cognate receptors, which are G-protein coupled, 7-transmembrane receptors. [78] Chemokines were initially shown to be involved in controlling the targeted migration of hematopoietic cells, but more recently they have been implicated in a diverse range of physiologic and pathologic functions, including wound healing, the control of angiogenesis, and the development of tumor metastases. Indeed, there has been an evolving interest in the role of chemokines and their receptors in the process of tumor metastasis in recent years. A landmark study clearly demonstrated that breast cancer cells that expressed the chemokine receptors CXCR4 and CCR7 were capable of preferentially homing to particular tissues. [79]

CCR7 is known to be the functional receptor for SLC (secondary lymphoid organ chemokine). It acts by influencing the migration of activated dendritic cells to regional lymph nodes. In a recent study, a strong association was reported between CCR7 expression and synchronous nodal metastasis in patients with tonsillar cancer. [80] Only 1 of 11 (9.1%) patients with a negative CCR7 immunohistochemistry had nodal involvement at presentation, in contrast to 8 of 13 (61.5%) patients with "+" staining, 24 of 27 (88.9%) patients with "++" staining, and 29 of 33 (87.8%) patients with "+++" staining. Similarly, the degree of CCR7 immunopositivity was directly correlated with the extent of nodal metastasis at diagnosis, such that 43 of 44 (97.7%) patients with N2 or N3 disease had "++" or "+++" immunostaining at diagnosis. CCR7 staining in the primary tumor was also shown to be associated with disease relapse, systemic metastasis, and disease-specific and overall survival.

Blockade of CCR7 signaling has been shown to increase the therapeutic efficacy of cisplatin and anti-EGFR therapy in murine models of SCCHN. [81] Similar effects in a breast cancer model have been reported with blockade of another chemokine receptor (CXCR4). [82] Clearly, this is an interesting area for future clinical development, although there have not yet been any clinical trials of targeted antichemokine therapeutics.


Despite significant improvements in the treatment outcome in patients with SCCHN that have resulted from technologic advances in radiation delivery and the use of cytotoxic chemotherapy, there is still a pressing need for novel therapies. In the last 2 decades, the molecular biology revolution has provided us with a new framework for developing specific targeted therapies. The first major success of this approach was the development of the anti-EGFR monoclonal antibody cetuximab, which has been shown to increase control rates in newly diagnosed disease (in combination with radiotherapy) and to prolong survival in relapsed disease (in combination with chemotherapy). This agent is likely to be the frontrunner of a series of new agents that will target specific molecular defects in head and neck cancer. It is likely that the next wave of developments will include active small molecule inhibitors of EGFR (and other members of the c-erbB family of receptors), antiangiogenic agents, and drugs that can increase proapoptotic signaling in cancer cells. As with cetuximab, it is most likely that these new agents will first find a niche in the context of combination regimens with standard anticancer therapeutics.


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