Seeking alternative biological therapies: The future of targeted molecular treatment

Oral Oncology 45 (2009) 447–453

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Oral Oncology journal homepage: www.elsevier.com/locate/oraloncology

Review

Seeking alternative biological therapies: The future of targeted molecular treatment Jochen H. Lorch *, Marshall R. Posner, Lori J. Wirth, Robert I. Haddad Dana Farber Cancer Institute, 44 Binney Street, SW430, Boston, MA 02115, United States

a r t i c l e

i n f o

s u m m a r y In recent years targeted therapies have expanded treatment options for patients with squamous cell cancer of the head and neck (SCCHN) considerably and have led to clinically significant benefit. However, the multitude of new targeted drugs that have emerged and are in development also represent a challenge and many years of carefully conducted clinical studies will be needed to explore their full potential. This article summarizes the most important recent developments in the targeted treatment of SCCHN and provides an overview of pathways and promising potential targets that could impact the treatment of patients with SCCHN in the future. Ó 2008 Elsevier Ltd. All rights reserved.

Introduction The treatment of squamous cell cancer of the head and neck (SCCHN) has become increasingly sophisticated in recent years and requires a multidisciplinary team combining the expertise from specialized surgeons, radiation and medical oncologists and support from other health professionals. With increasingly aggressive chemotherapy and chemoradiotherapy regimens, high response rates and improvements in survival have been achieved. Progress has now started to translate these gains into further clinically meaningful benefits in common practice. However, survival generally remains poor and we may now be close to or at a point where further increases in the efficacy of traditional combination chemotherapy and chemoradiotherapy are increasingly offset by increased toxicities. The advent of targeted therapies has already revolutionized many fields of oncology in the last decade. In head and neck cancer, the EGF receptor has long been recognized as an attractive target. Based on randomized Phase III and pure Phase II trials, EGF-R blocking treatments are now an established part of modern SCCHN care.1 With an improved understanding of molecular pathways and the increasing ability to discover and design new targeted drugs, the number of new agents has multiplied and it is estimated that currently more than 1000 compounds are in various stages of clinical development. It will take many years and the combined effort of the pharmaceutical industry, the medical community, patients and society as a whole to explore the vast opportunities that these new treatments offer and ensure further progress. The targets that are currently considered the most relevant in SCCHN and are explored therapeutically mostly fall into one of the following categories: Growth factor receptors, signal transduc-

* Corresponding author. E-mail address: [email protected] (J.H. Lorch). 1368-8375/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.oraloncology.2008.08.009

tion, angiogenesis, cell cycle control, protein degradation, and inducers of apoptosis. With an enormous number of compounds in various stages of development, a comprehensive overlook is beyond the scope of this article. The purpose is to provide an overview of the data that has emerged in recent years and to provide an image of the changing landscape that is beginning to emerge. Table 1 provides an overview of the targets and the drugs that are currently under development and that are undergoing clinical testing.

Growth factor receptors as targets EGF receptor The epidermal growth factor receptor (EGF-R) has been recognized as an attractive target for the treatment of SCCHN since it is over-expressed in >90% of cases.2 The EGF-R is a member of the Erb-B/HER family of receptors tyrosine kinases which also includes HER2, HER3 and HER4. The EGF-R possesses an extracellular N-terminal ligand binding domain, a transmembrane region and a C-terminal intracellular domain which includes the kinase domain and autophosphorylation sites. A series of EGF-R ligands have been identified, with most studies implicating transforming growth factor - a as the predominant autocrine growth factor in SCCHN. Binding of a ligand to the EGF-R triggers homodimerization of EGF-R or heterodimerization of EGF-R with other Erb-B receptors leading to autophosphorylation of the receptor and activation of the downstream signaling cascade. Currently, targeting the EGF-R has been achieved using three different approaches: (i) Antibody binding to the extracellular domain of the receptor with subsequent internalization of the antibody/receptor complex, (ii) competitive antagonism at the ATP binding site thus inhibiting EGF-R autophosphorylation and activation and (iii) down-regulation of the EGF-R by using antisense DNA or siRNA.

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Table 1 Molecularly targeted drugs in SCCHN Target category

Target molecule

Substance class

Example

Development in SCCHN phase

Growth factor receptor antagonist

EGF-R/erb-B

Monoclonal antibody

Cetuximab (Erbitux) Panitumumab (Vectibix) ABXEGF, EMD72000 Predominat EGF-R/erbB2 inhibitors: gefitinib (Iressa) erlotinib, (Tarceva) PKI166, GW572016 lapatinib (Tykerb) EGF-R and VEGF-R inhibitor: vandetanib (Zactima) EM164, AMG 479 NVP-ADW742

I–III, approved

Small molecule tyrosine kinase inhibitor

Signal transduction

Angiogenesis

IGF-R

Monoclonal antibody Small molecule

Ras

Small molecule

raf Met Farnesyl transferase MEK1/2

Small molecule Small molecule Non-peptide Small molecule

mTOR

Small molecule

VEGF

Monoclonal antibody

Zarnestra (R115777, tipifarnib) FTI Ras Inh: ISIS 5132 Sorafenib (Nexavar) SU11274 SCH66336 AZD6244, CI-1040, PD184352, PD 0325901 everolimus (RAD001)

Small molecule

bevacizumab (Avastin), VEGF trap (Aflibercept) sorafenib (Nexavar), sunitinib (Sutent), vandetanib (Zactima)

II

I I

I II I Preclinical II II

Cell cycle

Cyclin D1

Antisense

Protein degradation

Proteasome inhibitor (26S subunit)

Small molecule

Bortezomib

Preclinical

Inducers of apoptosis

APO2/Trail (agonist)

Monoclonal antibody Recombinant cytokine

AMG655 Apo2L/TRAIL (dulanermin)

I I

The chimeric monoclonal antibody Cetuximab (C225, ErbituxÒ) has become an established part of SCCHN treatment since it became first available approximately a decade ago. When used as single agent, the response rate is relatively modest around 10–15% with a disease-control rate of approximately 40–46%.3 A large, randomized trial compared PF alone with PF plus Cetuximab in 442 patients in first line therapy for recurrent disease.4 Overall survival was the primary endpoint. Median survival was 7.4 months in the PF arm compared with 10.1 months for the PFC arm (P = 0.036). This was one of the longest median survival times in this patient group ever recorded and the first randomized trial to demonstrate a survival advantage in the recurrent setting for head and neck cancer. Some questions remain regarding the value of the combination of PFC versus treating with PF followed by C on progression. However, based on these impressive data it is clear that patients with incurable SCCHN are likely to benefit from treatment with an EGF-R inhibitor at some point during their disease course. EGF-R therapy is not without toxicity. The acneiforme rash is frequent (80% overall, 3% severe) and interestingly correlates with a tumor response while EGF-R expression as measured by immune-histochemistry in this study was not a reliable predictor of tumor response.5 Due to the chimeric nature of this antibody, allergic reactions are found in approximately 3% of patients who receive Cetuximab and are more frequent in some geographic areas.6 The allergic reactions are due to carbohydrates added to the antibody during manufacturing.7 Several studies are evaluating Cetuximab in combination with Paclitaxel, or Docetaxel, in the recurrent disease setting and promising response rates including a significant number of complete responses have been reported as abstracts.8 Data from a randomized trial shows that the addition of Cetuximab to radiation for the definitive treatment of locally advanced SCCHN results in improved local control, overall survival and time to progression compared with radiation alone.9 In this landmark study in 424 patients with stage III and IV SCC of the oropharynx, hypopharynx, or larynx, the median duration of locore-

Preclinical

gional control was 24.4 months among patients treated with Cetuximab plus radiotherapy and 14.9 months among those given radiotherapy only (hazard ratio for locoregional progression or death, 0.68; P = 0.005). With a median follow-up of 54 months, the median duration of overall survival was 49 months among patients treated with combined therapy and 29.3 months among those treated with radiotherapy alone (hazard ratio for death, 0.74; P = 0.03). Radiotherapy plus Cetuximab significantly prolonged progression-free survival (hazard ratio for disease progression or death, 0.70; P = 0.006). Remarkably, there was no difference in the QOL between the two treatment groups.10 As a measure of global radiation toxicity, the rate of esophageal stenosis among survivors at 1 year was 17% with radiotherapy and 19% with the combination. Importantly, no effect on the rate of distant metastasis was noted. An unplanned analysis showed that patients with oropharynx primary and those who received concomitant boost radiation derived the most benefit from the combination.10 Despite these impressive results, it is still unclear whether there is a difference in outcome of Cetuximab combined with radiotherapy over platinum-based chemoradiation. An RTOG trial testing Cetuximab plus cisplatin based chemoradiotherapy with chemoradiotherapy alone is in progress. Studies using a similar, but fully humanized monoclonal anti-EGF-R antibodies such as Panitumumab are also underway. Activity as well as side effects appear similar to Cetuximab with a lower rate of severe allergic reactions. A number of EGF-R specific agents from the class of the small molecule tyrosine kinase inhibitors are available and are used in a variety of tumors, including SCCHN. They are competitive antagonists of the ATP binding site, inhibiting phosphorylation and subsequently activation of the EGF-R receptor. When used as single agents, the response rates appear comparable to those seen with anti-EGF-R antibodies. Studies led by investigators at the University of Chicago evaluated gefitinib (IressaÒ) in patients with recurrent SCCHN. 52 patients were treated with 500 mg gefitinib per day. Approximately half of the patients receiving gefitinib as

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second line therapy. An objective response was found in 10.6% and the disease-control rate was 53%. There appeared to be a dose dependence as the response rate to gefitinib at a lower dose (250 mg per day) induced responses is only 1.4%.11 A similar agent, erlotinib (TarcevaÒ), has been tested in patients with recurrent disease and the response rate was 4% with a progression-free survival and overall survival similar to that seen with gefitinib.12 There is some evidence that response to erlotinib may be more likely in patients with a high EGF-R copy number indicative of EGF-R amplification.13 The side effects of the small molecule tyrosine kinase inhibitors are remarkably similar to the EGF-R antibodies and involve the acneiforme skin rash, diarrhea and electrolyte disturbances, most notably hypocalcemia and hypomagnemia which are thought to be directly linked to the blocking of EGF-R dependent renal reabsorption. Combined with cisplatin and docetaxel, erlotinib demonstrated a response rate of 67% with 4/43 patients achieving a complete response. Median overall survival was an impressive 11 months (8.61, 22.5, 95% CI) and progression-free survival was 6.01 months (4.37, 8.25, 95% CI). However, side effects were significant with 6 patients who had grade 3/4 febrile neutropenia, 4 patients had grade 3/4 dehydration, 3 patients had grade 3 diarrhea, and 2 patients had grade 3/4 GI bleeding.14 Erlotinib has also been combined with the VEGF inhibitor Bevacizumab and a recent update suggests a higher response rate compared with erlotinib alone. In this trial, median overall/ progression-free survival was 7.3 months/3.9 months with 30.6% and 8.2% of patients alive at 1 and 2 years. In a phase I study, gefitinib was combined with the cyclooxygenase-2 inhibitors celecoxib at several dose levels in patients with recurrent or unresectable SCCHN who had received at least one prior chemotherapy regimen. Side effects were mild and four of 18 patients assessable for response (22%) achieved a confirmed partial response.15 The frequent coexpression of the EGF-R with HER2 and multiplying effects of heterodimerization on EGF-R signaling has led to studies investigating the effects of the dual receptor antagonist lapatinib (GW572016, TykerbÒ). While toxicity was mild, disappointingly little clinical activity was observed in patients with recurrent/metastatic SCCHN, some of which had previously been exposed to EGF-R inhibitors.16 The third antiEGF-R strategy involves the down-regulation of the EGF-R receptor by direct injection of antisense DNA. Data from a phase 1 trial suggests that this approach is well tolerated and tumor responses were seen. This may be a useful strategy in specialized centers.17 One drawback of these reagents is the need for direct injection and accessibility of all tumor sites. Phase II trials and innovative delivery methods may make agents such as this more widely useable in both curative and palliative settings. Insulin-like growth factor receptor A number of other growth factor receptor antagonists have been developed and are currently undergoing clinical testing. The insulin-like growth factors and specifically IGF-I along with its IGF-binding protein 3 (IGFBP-3) have been implicated in cancer progression and metastasis.18,19 IGF-I acts though the IGF receptor 1 (IGF- R1), which allows IGF-I to exert its mitogenic effect on both normal and cancer cells. The IGF-IR is a receptor tyrosine kinase which activates Ras and phosphatidylinositol 30 -kinase-related signal transduction pathways and is involved in angiogenesis, can suppress cellular apoptotic pathways and facilitates cell growth, all of which make it an attractive therapeutic target in many solid tumors including head and neck cancer. Interestingly, serum IGF-1 and serum IGFBP-3 levels have also been found to predict second primary cancer risk.20 Similar to EGF-R inhibition, strategies to block the IGF-IR receptor include monoclonal antibodies, small

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molecule tyrosine kinase inhibitors as well as a variety of modulators of IGF-R1 gene expression. IGF-R1 inhibition in combination with traditional chemotherapy agents are planned or in progress and results are pending. Preclinical SCCHN models suggest that combinations with EGFinhibitors may result in enhanced efficacy since the effects of EGF-R inhibition may depend on cross-talk between EGF- and IGR- receptors.21 c-Met Hepatocyte growth factor (HGF), also known as a scatter factor, regulates a variety of biological activities including cell proliferation, survival, migration, and angiogenesis. Importantly, HGF and its receptor c-Met have been found to be associated with metastasis of SCCHN making c-Met expression a potentially useful prognostic marker as well as an attractive therapeutic target.22–24 Preclinical models suggest HGF may be an important growth factor in SCCHN.25 To date, no studies have been published in SCCHN patients undergoing therapy with c-Met inhibitors but several trials are under way to explore antibody-based and small molecule tyrosine kinase inhibitors that target c-Met in patients with recurrent SCCHN.

Signal transducers The Ras/Raf pathway EGF-R activation triggers activation of a number of phosphorylation events in downstream cascades which include the Ras/raf/ Erk/MEK pathway, the src/Jak/stat and the PI3 K, AKT and m-TOR pathway (Fig. 1), respectively. The Ras superfamily of GTPases comprises several subfamilies of small GTP-binding proteins including H-ras, K-ras, and N-ras and are major checkpoints that control a wide array of cellular functions in normal and malignant cells. They bind the guanine nucleotides guanosine triphosphate (GTP) and guanosine diphosphate (GDP). Ras bound to GTP (RasGTP) is the ‘‘active’’ form with which downstream effector proteins specifically interact, thus propagating intracellular signals. Ras activates one of the major mitogenic and survival pathways in normal human cells. Raf is a primary target of activated Ras and activated raf, non-receptor tyrosine kinase, activates MEK family kinases, which are activators of map kinases (ie: Erk). The Ras signaling pathway is well-described, and has been implicated in regulation of cellular motility, invasiveness, and immortality, respectively. Unlike many other types of cancer, mutations in Ras genes are actually rare in SCCHN. However, members of the Ras family are over-expressed in SCCHN and nasopharyngeal cancer (NPC) and in vitro evidence suggests that the level of K-ras expression is a determinant of proliferation of SCCHN cell.26 Recent data in colon cancer suggests that the presence of k-ras mutations offers tumor cells protection against antiEGF-R therapy, but it is not clear whether this also applies to SCCHN.27 Activation of one member of the Ras family proteins, H-ras, depends on anchoring of the protein to the cell membrane in a farnesylation-dependent process called prenylation. As would be expected for an inhibitor of such a fundamental molecular process, farnesyl transferase inhibitors are modulating a multitude of biologic pathways and processes beyond H-ras, including AKT degradation.28 Farnesyl transferase inhibitors have been tested in patients with SCCHN using SCH66336 for 2 weeks prior to definitive surgery. As expected, protein farnesylation diminished and interestingly, although treatment was short and response rate was not a major endpoint of the study, two partial and two minor

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Figure 1. Schematic representation of tyrosine kinase signaling through Ras and Pi3K/AKT/mTOR mediated signaling pathways. Other pathways such as the JAK/STAT pathways are not included since these pathways are currently not tested clinically as therapeutic targets in SCCHN.

responses were observed. In a study with recurrent SCCHN, treatment with SCH66336 resulted in stable disease in 6/15 patients but no objective responses were seen in this heavily pretreated population. Side effects were mild.29 Raf The Raf serine/threonine kinases are key downstream effectors of Ras activation in the mitogen-activated protein kinase (MAPK) pathway. Raf activation occurs immediately downstream of membrane and cytoplasmic receptors that relay mitogenic signals. Although principally activated by Ras, Raf may also be activated by Ras-independent signals through activation of further effectors and, similar to Ras, propagates signals through diverse effectors that mediate proliferation, angiogenesis, metastases, and survival.30 Raf may be activated by signaling upstream or constitutively by mutation. Constitutive activation of Raf and Ras are indistinguishable in their potential to induce malignant transformation and have been described in many solid tumors although the frequency or Raf activating mutations in SCCHN appears to be low.31

Sorafenib is a small molecule tyrosine kinase inhibitor and has significant C-Raf and B-RAF inhibiting activity. It also inhibits MEK and ERK phosphorylation in addition to its antiangiogenic effects as a strong antagonist of VEGF receptors 2 and 3 and the PDGF receptor. In a phase II trial 44 patients with recurrent SCCHN received sorafenib (400 mg twice daily) and the results were recently presented in abstract form. Although the overall response rate was disappointing low (3%), the progression-free survival of 4 months was encouraging.32 Another phase 2 trial reported similar objective response and stable disease rates.33 The fairly high number of patients with stable disease raised the question whether Sorafenib may have a role in maintaining disease stability rather than inducing a reduction in tumor size. Overall, the side effects were fairly mild with few grade 3 or 4 toxicities. Typical side effects reported in these studies include hand/foot syndrome, stomatitis, anorexia as well as other rare but serious effects such as pulmonary embolism. Data from trials in patients with different tumors suggest that potentially fatal gastric perforations occur between 0.1 and 0.01% of cases. Other similar small molecule tyrosine kinase inhibitors are currently undergoing clinical testing but results are not yet available.

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Other inhibitors targeting this pathway are MEK and ERK inhibitors some of which have been tested in preclinical SCCHN cells and have shown promising activity. While some have recently entered clinical testing, no results are available to date. mTOR The mammalian target of rapamycin (mTOR), also known as rapamycin-associated protein, rapamycin target, or sirolimus effector protein, is a 289 kDa serine/threonine kinase that is intimately linked with protein synthesis and is a central integrator of growth factor signaling. Regulation of mTOR pathway activation is mediated through a series of complex signaling events linking growth factor receptor signaling, phosphatidylinositol 3-kinase activation (PI3 K), and activation of the Akt/protein kinase B pathway. mTOR phosphorylation and activation in turn activates p70 S6 kinase, leading to enhanced translation of ribosomal proteins and elongation factors. This leads, among other effects, to the production of hypoxia-inducible factor-1a, a regulator of gene transcription that stimulate cell growth and angiogenesis, including VEGF. The second major mTOR effect is on the 4E-binding protein-1 and eukaryotic initiation factor-4 subunit E complex. Activated mTOR phosphorylates 4E-binding protein-1, ultimately leading to an increase in the translation of mRNAs that encode cell cycle regulators, such as c-myc, cyclin D1, and ornithine decarboxylase.34 Thus, mTOR is at the center of multiple crucial pathways regulating a wide variety of critical molecular mechanisms and processes. Many abnormalities in various components of the mTOR pathway have been described for a wide variety of sporadic malignancies, including SCCHN.35–37 mTOR inhibitors have been used for many years as immunosupressants in human organ and bone marrow transplantation. As the key role of mTOR in the PI3 K and AKT signaling pathways, which are frequently aberrant in malignant cells, was elucidated over the last decade, inhibitors and newer less toxic agents have been studied for several years and have shown promising activity in preclinical SCCHN tumor models. Defective PTEN appears to convey sensitivity to mTOR inhibition.38 Interestingly, data suggests that the combination of EGF-R and mTOR inhibition might result in synergistic anti-tumor effects.39 Clinical trials testing the mTOR inhibitor everolimus in combination with cisplatin, Cetuximab and radiotherapy in patients with locally advanced SCCHN as well as mTOR inhibitors with chemotherapy agents in recurrent disease are ongoing but no clinical data has been published to date. Angiogenesis Angiogenesis is critical for tumor growth and metastasis. It is a highly regulated process which relies on an intricate network of pro-angiogenic and angiogenesis-inhibiting events intended to control tissue blood supply. A multitude of receptors and pathways are involved in this process and include members of the VEGF receptor family, platelet derived growth factor, Kit, TGF-a, TGF-b, fibroblast growth factor and interleukin 8, among others. The vascular endothelial growth factor (VEGF) and the VEGF receptors (VEGF-R) VEGFR 1 (Flt1), VEGFR-2 (Flk2/KDR) and VEGFR-3 (flt4), have emerged as key targets for antineoplastic agents in recent years. Bevacizumab (AvastinÒ) is a recombinant humanized monoclonal antibody directed against VEGF. Bevacizumab binds to VEGF and inhibits VEGF receptor binding, thereby preventing the growth and maintenance of tumor blood vessels. Bevacizumab has been approved in non-small cell lung cancer, colon cancer and recently also in breast cancer based on survival data. It has limited single agent activity but appears to substantially interact with more traditional chemotherapy agents. Given the risk of sometimes fatal pulmonary hemorrhage in patients with

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squamous cell NSCLC, there has been a certain reluctance to study this drug in SCCHN. Recently, however, data has emerged that suggests that at least in selected cases, it can safely be administered in SCCHN patients. An ongoing phase II trial using the combination of bevacizumab and the EGF-R inhibitor erlotinib in patients with recurrent SCCHN demonstrated an encouraging overall response rate of 14.6%.40 A study exploring bevacizumab as a radiation sensitizer in combination with 5FU and hydroxyurea, both potent radiosensitizers themselves, is currently ongoing. Side effects as with other antiangiogenic agents include hypertension and there is a risk for bowel perforation. The rise in serum VEGF levels is well documented during treatment with bevacizumab although the level of unbound VEGF is undetectable.41 Nonetheless, uncertainty exists whether the reactive rise in VEGF may promote tumor growth after bevacizumab is stopped. Similar anti-VEGF agents such as VEGF-Trap (aflibercept) are in development but have not been tested in SCCHN thus far. As described above, the oral tyrosine kinase inhibitor sorafenib that inhibits VEGFR-1 and 2 resulted in a fairly high rate of stable disease32,33 Similar agents such as vandetanib (ZactimaÒ) which possesses anti-EGF-R activity in addition to VEGF-R inhibition is currently undergoing clinical testing in combination with docetaxel. Cell cycle inhibitors Cell cycle dysregulation is a hallmark of cancer resulting in unchecked cell growth and tumor formation. Inhibition of cyclins (cyclins A, B, D and E), cyclin dependent kinase (CDK1, 2, 4 and 6) as well as restoration of CDK inhibitors (p15, p16, p21 and p27) have long been recognized as potential targets a number of drugs have become available during the last decade. Molecules that target CDK’s have been used in SCCHN including bryostatin1, flavipiridol, UCN-01 and perifosine. Despite promising preclinical results, results from phase II trials with Bryostatin-1 in patients with recurrent or metastatic SCCHN, failed to show significant activity. Flavipiridol, a synthetic flavone, failed to show systemic activity in phase 2 trials in SCCHN as well and was associated with significant toxicity. UCN-01 (7hydroxystaurosporine) has PKC, CDK- and chk1- inhibiting properties and also showed similar promise in preclinical testing.42 In phase 1 and 2 trials in SCCHN, however, toxicity was significant and to date no data on effectiveness has been published. Other strategies to target cyclin D1, which is frequently overexpressed in SCCHN, involve the down-regulation with an adenoviral antisense cyclin D1 vector have been successfully in laboratory tests but currently no trials are under way to explore this strategy. Protein degradation Proteasome inhibitors target the degradation of proteins that have undergone ubiquination which labels them for subsequent breakdown. Since the majority of intracellular proteins are regulated at least in part by this process, proteasome inhibition affects a wide range of molecular processes and pathways including cell cycle blockage due to inhibited cyclin clearance, caspase induction, IAP stability, p53 accumulation, and NF-jB inhibition. A major role seems to be exerted by NF-jB degradation although it is unclear whether there is a predominant pathway responsible for the anti-tumor activity.43 In preclinical models, SCCHN cells were exquisitely sensitive to bortezomib (VelcadeÒ, formerly known as PS-341) and trials to test the clinical activity are planned. Drug safety is favorable as the use in other malignant diseases has shown and side effects are manageable. Preclinical data also suggests that bortezomib in combination with an EGF-R inhibitor

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may be a particularly useful combination in SCCHN since bortezomib up-regulates the EGF-R and tumor cell death rate suggests at least additive anti-tumor effects.44 Inducers of apoptosis Dysregulated apoptosis plays a key role in the pathogenesis and progression of neoplastic disorders, allowing tumor cells to survive beyond their normal life span and to eventually acquire chemoradioresistance. Apoptosis is regulated by a number of proteins present as receptors on the cell surface, intracytoplasmic inhibitors and intranuclear proteins. Apoptosis can be triggered through a number of pathways. p53, a tumor suppressor whose gene is frequently altered in SCCHN, is a nuclear protein that facilitates apoptosis under conditions of irreparable DNA damage. The mechanisms through which p53 activates apoptosis include expression of proteins involved in direct mitochondrial-associated apoptotic events, up-regulation of cell cycle inhibitors, and finally through induction of apoptosis-inducing receptors such as Fas and members of the tumor necrosis factor (TNF)–related apoptosis-inducing ligand receptor (TRAIL-R) family. Another pathway that results in apoptosis proceeds through Apo2L/TRAIL, which belongs to the TNF family of death receptor ligands. Apo2L/TRAIL interacts with 5 distinct receptors belonging to the TNF receptor superfamily. TRAIL binds to death receptor 4 (DR4/TRAIL-R1) and death receptor 5 (DR5/TRAIL-R2), which are expressed on the cell surface of many cancer cells. Ligation of DR4 or DR5 is accomplished by recruitment of an adaptor protein, Fas-associated death domain (FADD), to the death receptor. This ultimately leads to caspase activation and apoptosis.45 DR/TRAILR is expressed in a significant number of SCCHN cases and somatic polymorphisms of death receptor 4 (DR4/TRAIL-R1) are frequent suggesting a role of this pathway in SCCHN progression.46 AMG 655 is a fully human monoclonal agonist antibody that binds human TRAIL receptor 2 (TR-2/DR5), thus mimicking the activity of native TRAIL, activating TR-2 and thereby inducing tumor cell apoptosis. Phase I data suggests that it is well tolerated and partial responses in patients with NSCLC were seen. No experience exists to date in SCCHN patients. Recombinant human Apo2L/TRAIL (dulanermin) which activates DR4/ TRAIL-R and DR5/TRAIL-R2 is also in clinical development but no data in SCCHN patients has been published. Strategies to up-regulate p53 activity have been tested and although scientifically intriguing, clinical effectiveness of these agents has been transient and somewhat disappointing thus far.47,48

Conclusion and future directions Decades of basic science research and improved understanding of cancer biology have resulted in a plethora of new drugs that are now reaching the bedside and have begun to transform clinical care. Although the early initial enthusiasm spawned by dramatic successes of targeted therapeutics in diseases like CML and GIST may have been premature for many solid tumors including SCCHN, it is clear that these drugs hold the key to further improvement and progress has been made. Based on data that is currently available, it appears that the most promising strategies using targeted drugs in SCCHN is in combination with traditional chemotherapy agents and/or radiation and we will likely see a large number of conventional/targeted drug combinations to emerge in the near future. It is also evident that a lot more work needs to be done. As we move forward with the design and implementation of new treatment protocols, the use of predictive markers that indicate an individual patient’s susceptibility to a particular drug will be essential

in order to maximize the potential that these new therapies offer. For example, it is likely that HPV associated oropharyngeal SCCHN depends on mechanisms that could be exploited by a particular drug while in tumors with a different etiology other drug combinations may be more beneficial. These studies will be crucial to fully explore the possibilities that targeted therapies offer and prevent the premature dismissal of drugs as inactive in an unselected population. We believe that these investigations should have priority as they will be necessary to ensure further progress. These are exciting times in medical oncology in general and the treatment of SCCHN in particular. With many new drugs being tested and more in early stages of development, improved understanding of biologic processes from basic science, careful panning and the meticulous execution of innovative clinical trials will be key to further treatment advances. With this in mind, progress will be made and patients and their families will continue to benefit. Conflict of Interest Statement The authors report the following disclosures with Pharmaceutical Firms and Oncology Agencies for last 12 Months: Jochen H. Lorch, MD – Honoraria: None; Clinical Research: Novartis, Amgen; Consultant: Onyx Pharmaceuticals; Member: ASCO, AACR; Stock: None; Significant Income From Above: None; Financial Relationship: None Marshall R. Posner, MD – Honoraria: Sanofi Aventis, Imclone; Clinical Research: Abraxis, Sanofi aventis, Astrazeneca, Bristol Myers Squibb, Genentech, OSI, Amgen, NCI, NIAID, Imclone; Consultant: Amgen, Glaxo-Smith-Kline, NCI, BMS, Sanofi-Aventis, Oxigene, Imclone, DNAR, Promedior, Novartis, Merck, EMD Serono, Biovex; Member: ASCO, AACR, ASH, AAI, NCCN, RTOG, ESMO; Stock: None; Significant Income From Above: None; Financial Relationship: None Lori J. Wirth – Honoraria: Sanofi-Aventis; Clinical Research: OSI, Amgenl; Consultant: none; Member: ASCO, NCCN; Stock: None; Significant Income From Above: None; Financial Relationship: None Robert I. Haddad – Honoraria: Sanofi Aventis, Bristol Myers Squibb; Clinical Research: None; Consultant: Sanofi-Aventis; Member: ASCO, AACR, NCCN; Stock: None; Significant Income From Above: None; Financial Relationship: None References 1. Forastiere AA, Burtness BA. Epidermal growth factor receptor inhibition in head and neck cancer–more insights, but more questions. J Clin Oncol 2007;25:2152–5. 2. Grandis JR, Tweardy DJ. Elevated levels of transforming growth factor alpha and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer Res 1993;53:3579–84. 3. Vermorken JB, Trigo J, Hitt R, et al. Open-label, uncontrolled, multicenter phase II study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy. J Clin Oncol 2007;25:2171–7. 4. Vermorken JB, Mesia R, Vega V, et al. Cetuximab extends survival of patients with recurrent or metastatic SCCHN when added to first line platinum-based therapy – results of a randomized phase III (extreme) study. Proc Am Soc Clin Oncol, 2007 abstract #6091. 5. Kies MS, Ghebremichael MS, Katz TL, Herbst RS, Youssoufian H, Burtness B. EGFR expression by immunohistochemistry (IHC) and response to chemotherapy and cetuximab in squamous cell carcinoma of the head and neck (SCCHN). Proc Am Soc Clin Oncol 2007;25. abstract #6024. 6. O’Neil BH, Allen R, Spigel DR, et al. High incidence of cetuximab-related infusion reactions in tennessee and North Carolina and the association with atopic history. J Clin Oncol 2007;25:3644–8. 7. Chung CH, Mirakhur B, Chan E, et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1, 3-galactose. N Engl J Med 2008;358:1109–17. 8. Hitt R, Irigoyen A, Nuñez J, et al. Phase II study of combination cetuximab and weekly paclitaxel in patients with metastatic/recurrent squamous cell carcinoma of head and neck (SCCHN): Spanish head and neck cancer group (TTCC). Proc Am Soc Clin Oncol 2007;25. abstract #6012.

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