Current Cancer Therapy Reviews - Volume 3, Issue 4, 2007

Growth factors are locally secreted peptide hormones that are involved in regulating cell proliferation, differentiation and survival by binding to and by activating specific cell membrane receptors on target cells. The epidermal growth factor (EGF) is the first discovered growth factor within a family of related proteins (EGF-like growth factors), which includes transforming growth factor ?? (TGF??), amphiregulin, heparin binding-EGF (HB-EGF), epiregulin, heregulins, neuregulins, and betacellulin [1-3]. EGF-like growth factors bind to and activate one or more receptors of the ErbB family which is composed of four members: the EGF receptor (EGFR) (also known as ErbB1/HER1), ErbB-2 (Neu/HER2), ErbB-3 (HER3) and ErbB-4 (HER4) [1-3]. The EGFR is a 170 kDa transmembrane glycoprotein with an extracellular domain, a hydrophobic transmembrane domain, and an intracellular region containing the tyrosine kinase domain. EGF, TGF?? and amphiregulin are the specific ligands for the EGFR and are commonly produced by the majority of human epithelial cancers. The EGFR exists on the cell membrane as inactive monomers, which dimerize following ligand activation. Depending on the ligand and on the presence of other receptors of the ErbB family, EGFR-EGFR homo-dimers or hetero-dimers between the EGFR and another member of the EGFR family may be formed. In any case, following ligand binding, the tyrosine kinase intracellular domain of the receptor is activated, with autophosphorylation of the intracellular domain, which initiates an intracellular signalling cascade [1-3]. In this respect, EGFR activation is critical for cell proliferation, but also contributes to angiogenesis, invasion, metastasis and inhibition of apoptosis [2]. Activation of the TGF??-EGFR autocrine growth pathway is a common mechanism for autonomous, dysregulated cancer cell growth in the majority of human epithelial cancers. Several mechanisms have been described which are responsible for an uncontrolled activation of this autocrine growth pathway, such as receptor overexpression, increased ligand concentration, decreased receptor turnover, or the presence of aberrant receptor proteins. In this respect, different somatic activating EGFR gene alterations, including small in-frame deletions, point mutations, gene amplification or increased gene copy numbers, and large gene deletions, such as the type-III variant (EGFRvIII), which lacks a portion of the extracellular domain with constitutive, ligand-independent EGFR activation, have been reported in human cancers [1-3]. Overexpression of EGFR and/or TGF?? has been generally associated with advanced disease and poor prognosis and with the development of resistance to chemotherapy, radiotherapy and/or hormonotherapy [4-6]. The results of a large body of preclinical studies and clinical trials suggest that targeting the EGFR could provide a contribution to cancer therapy. Among several potential strategies for targeting EGFR-driven signals, two have reached a therapeutic success in human cancer therapy: the use of EGFR blocking monoclonal antibodies (MAbs) and of small molecules EGFR tyrosine kinase inhibitors (TKIs). MAbs are genrally raised against the EGFR extracellular domain to block ligand binding and receptor activation. TKIs prevent EGFR autophosphorylation and activation since they are direct inhibitors of ATP for binding to the intracellular EGFR tyrosine kinase catalytic domain. Although both types of agents are directed against the same target, they are structurally and functionally different molecules with different pharmacologic characteristics which could be responsible of different therapeutic activities (Table 1). In this respect, MAbs are generally directed against the extracellular domain of the EGFR and are highly specific and selective since they bind exclusively to the EGFR. These immunoglobulins need to be administered intravenously. Following binding to the receptor, MAbs induce intracellular EGFR internalization with subsequent EGFR down-regulation on the cancer cell membrane. In addition, anti-EGFR MAbs can elicit potentially therapeutic immnue functions in the host, such as antibody-dependent cellular cytotoxicity (ADCC), an antitumor mechanism which could be relevant in vivo, as it has been shown for other closely related mAbs, such as the anti-erbB2 mAb trastuzumab [7]. The currently available anti-EGFR MAbs are second generation MAbs. In fact, the first mouse-derived anti-EGFR MAbs had some important therapeutic limitations due to the induction of a human anti-mouse immune response in the majority of patients with the production of human neutralizing anti-mouse immunoglobulins, which were responsible of a consequent rapid clearance of the murine MAb, with limited tumour targeting and therapeutic activity. To overcome this problem, strategies aimed to decrease the immunogenicity of the antibodies have been developed. In this respect, chimeric and humanized MAbs have been engineered by replacing the mouse constant immunoglobulin domains with the corresponding human constant domains [8]. A further improvement has been obtained with the generation of fully human anti-EGFR MAbs [8,9]. On the other hand, anti-EGFR TKIs are low molecular weight compounds which could be administered orally with a daily continous dosing. These molecules possess a different range of specificity against the EGFR. In fact, some anti-EGFR small molecule TKIs are relatively selective for the EGFR, whereas other drugs are also able to efficiently inhibit the tyrosine kinase activity of other members of the erbB/HER family or of other cell membrane tyrosine kinase receptors belonging to other families such as the vascular endothelial growth factor receptor (VEGFR) family. Moreover, anti-EGFR TKIs could differ also for their reversible or irreversible inhibition of the tyrosine kinase activity [10-12]. Recently, a series of somatic in-frame small deletions or pointmutations in specific exons of the EGFR gene which correspond to the ATP binding site pocket in the EGFR protein have been described in a subset of non-small cell lung cancer patients as conferring an increased sensitivity to the antitumor activity of some anti-EGFR TKIs, such as gefitinib and erlotinib [13-15]. However, the presence of these mutant EGFRs does not change the sensitivity to anti-EGFR blocking MAbs, which are able to inhibit cancer cells proliferation independently from receptor mutations [16]. The aim of the present hot topic issue of Current Cancer Therapy Reviews is to provide to the reader a series of review articles which summarize the currently available preclinical and clinical data and the relevant open clinical issues for the optimal use of anti-EGFR directed therapeutic approaches in cancer treatment. A series of clinically relevant problems in this field have been selected and will be discussed, including: 1, the current clinical results on the use of anti-EGFR drugs in nonsmall cell lung cancer (NSCLC) and in colorectal cancer (CRC): 2, the clinical development of anti-EGFR TKIs which could inhibit other relevant growth factor receptor targets such as the VEGFRs; 3, the combination of anti-EGFR agents and radiation therapy in the treatment of head and neck squamous cell carcinoma (HNSCC); 4, the identification of clinical and molecular characteristics which could help to better select cancer patients that are candidate to treatment with EGFR targeted drugs; 5, the clinically relevant problem of intrinsic and acquired resistance to treatment with anti-EGFR agents: 6, the possibility of combining anti-EGFR drugs with other agents which target other molecular pathways which are relevant for cancer development and progression; 6, the methodology issues that the clinical development of molecularly targeted agents such as anti-EGFR drugs have opened for a correct design of clinical trials which could be useful in defining the activity and the efficacy of these drugs in the treatment of human cancers. REFERENCES [1] Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 1995; 19: 183-232. [2] Kuan CT, Wikstrand CJ, Bigner DD. EGF mutant receptor vIII as a molecular target in cancer therapy. Endocr Relat Cancer 2001; 8: 83-96. [3] Moscatello DK, Holgado-Madruga M, Godwin AK, et al. Frequent expression of a mutant epidermal growth factor receptor in multiple human tumors. Cancer Res 1995; 55: 5536-5539. [4] Nishikawa R, Ji XD, Harmon, RC, et al. A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. Proc Natl Acad Sci U S A 1994; 91:7727-7731. [5] Rubin Grandis J, Melhem MF, Gooding WE, et al. Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst 1998; 90: 824-832. [6] Rusch V, Baselga J, Cordon-Cardo C, et al. Differential expression of the epidermal growth factor receptor and its ligands in primary non-small cell lung cancers and adjacent benign lung. Cancer Res 1993; 53(10 Suppl): 2379-2385. [7] Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med 2000; 6: 443-446. [8] Trikha M, Yan L, Nakada MT. Monoclonal antibodies as therapeutics in oncology. Curr Opin Biotechnol 2002; 13: 609-614. [9] Ezzell C. Magic bullets fly again. Sci Am 2001; 285: 34-41. [10] Ciardiello F, Tortora G. A novel approach in the treatment of cancer: targeting the epidermal growth factor receptor. Clin Cancer Res 2001; 7: 2958- 2970. [11] Grunwald V, Hidalgo M. Developing inhibitors of the epidermal growth facto receptor for cancer treatment. J Natl Cancer Inst 2003; 95: 851-867 [12] Mendelsohn J, Baselga J. Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 2003; 21: 2782- 2799. [13] Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 2004; 304: 1497- 1500. [14] Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350: 2129-2139. [15] Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from ‘‘never smokers’’ and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 2004; 101: 13306-13311. [16] Mukohara T, Engelman JA, Hanna NH, et al. Differential effects of gefitinib and cetuximab on non-small-cell lung cancers bearing epidermal growth factor receptor mutations. J Natl Cancer Inst 2005; 97: 1185-94.

The epidermal growth factor receptor (EGFR) is a cellular transmembrane receptor with tyrosine kinase enzymatic activity which plays a key role in human cancer. EGFR-dependent signaling is involved in cancer cell proliferation, apoptosis, angiogenesis, invasion and metastasis. Targeting the EGFR has played a central role in advancing non small cell lung cancer (NSCLC) research, treatment and patients outcome over the last several years. Two types of anti-EGFR targeting agents have reached advanced clinical development: monoclonal antibodies (Mabs) and small molecule inhibitors of the EGFR tyrosine kinase enzymatic activity (TKIs). Among TKIs gefitinib and erlotinib has been approved for the treatment of advanced NSCLC. Some clinical features such as never-smoking, female gender, East Asian origin, adenocarcinoma histology, and some biological characteristics such as somatic EGFR gene mutations and increased EGFR gene copy number, are associated with a greater benefit from treatment with TKIs. This review focuses on the clinical evidence on the anticancer activity of EGFR-TKIs in the treatmnent of NSCLC patients.

Angiogenesis, the formation of new blood vessels from the endothelium of the existing vasculature, is fundamental to support tumor growth. Inhibiting tumor angiogenesis is a promising strategy for treatment of cancer and has been successfully transferred from preclinical to clinical application in recent years. Due to its role in tumor angiogenesis, the vascular endothelial growth factor (VEGF) and its receptor have been a major focus of basic research and drug development in the field of oncology. Vandetanib, is an orally bioavailable inhibitor of VEGF receptor-2 tyrosine kinase activity that in preclinical studies has been shown to inhibit both VEGF-induced signalling in endothelial cells and tumourinduced angiogenesis. Consistent with inhibition of angiogenesis, vandetanib, produced significant broad-spectrum antitumour activity in a panel of histologically diverse human tumour xenografts. In addition to its antiangiogenic properties, vandetanib also has activity against the epidermal growth factor receptor (EGFR) tyrosine kinase, which could impart a direct inhibitory effect on tumour cell growth and survival. Early clinical evaluation of this agent has demonstrated a safety profile and comprehensive series of phase II studies have clarify the value of this approach in the treatment of solid tumor. This review summarises preclinical and clinical studies with this unique agent.

Colorectal cancer (CRC) is the fourth most common malignant disease. Of newly diagnosed patients, 40% have metastatic disease at diagnosis, and approximately 25% of patients with localized disease at diagnosis will ultimately develop metastatic disease. The benefits of systemic chemotherapy in the treatment of metastatic colorectal cancer over best supportive care have been established. The epidermal growth factor receptor (EGFR) is overexpressed in the 80% of colorectal cancer and correlate with a poor prognosis. Cetuximab (C225, Erbitux TM) is chimeric human-mouse G1 immunoglobulin that binds to the EGFR with a 10-fold higher affinity than the natural ligands TGF?? and EGF. Cetuximab is currently licensed worldwide for the treatment of irinotecan-refractory metastatic CRC disease. It is well tolerated and the major adverse event is skin rash which also correlates with clinical response to treatment. An extensive phase II and III program of evaluation of cetuximab activity and efficacy in different settings of metastatic CRC has been undertaken. This article will review the current knowledge on the role of cetuximab in the medical management of metastatic CRC.

Panitumumab is a fully human monoclonal antibody directed against the epidermal growth factor receptor (EGFR), which when overexpressed may contribute to the development and progression of cancer and is present in several solid tumors, including colorectal cancer (CRC). Panitumumab is registered in USA for the treatment of patients with EGFR expressing CRC after disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecancontaining chemotherapy regimens. The present evidence of effectiveness of Panitumumab for the treatment of metastatic CRC is based on objective tumor respose as well as on progression-free survival. This review article summarizes the development of Panitumumab in preclinical and early phase trials in CRC and focuses on the most recent results available from advanced phase clinical trials, with an update on presentations at the 2007 annual meeting of the American Society of Clinical Oncology (ASCO).

Epidermal growth factor receptor (EGFR) signalling has previously been identified as an important prognostic factor in patients with head and neck cancer (HNC). EGFR has been confirmed in a phase III randomized trial as a critical target in combination with radiation therapy for locally advanced HNC patients. Provocatively, the outcomes, at first glance, appear similar to patients treated with conventional chemo-radiation; but with less mucosal toxicity. Promising options for EGFR inhibition include targeting the epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors (EGFR-TKIs), and monoclonal antibodies to prevent ligand binding. There are limitations to EGFR inhibition as only 10% of patients respond to EGFR blockade with advanced disease; therefore, immunohistochemistry, fluorescence in situ hybridization (FISH), gene arrays and molecular analysis techniques have been performed in an effort to predict which patients will respond to EGFR targeted therapies. Are there new issues and discoveries regarding EGFR biology that will provide information to determine at the outset, which patients will respond to this type of therapy, and which patients will benefit from alternative “targeted agents”? In development are agents that target selective parts of the EGFR pathway such as Akt, mTor or Src kinase inhibitors. Novel drugs attacking both the EGFR and angiogenic pathways may provide wider applicability and improve radiation response further. This review will update head and neck specialists as to relevant new information regarding EGFR inhibition, alternative approaches with targeted agents and challenges facing oncology investigators to better define the appropriate patient population to benefit from these new agents.

Molecules interfering with the Epidermal Growth Factor Receptor (EGFR) have been successfully tested in several human malignancies in the last decade, including non-small cell lung cancer, colo-rectal, pancreatic and head and neck cancer. Particularly, the two most commonly used strategies for blocking EGFR include tyrosine-kinase inhibitors (TKIs) targeting the intracellular domain of the receptor and monoclonal antibodies (MAb) directed against its external portion. One of main goals of researchers is to identify biological predictors of activity or resistance to these agents, both for ethical and pharmacoeconomical reasons. EGFR protein expression assessed by immunohistochemistry does not seem to accurately predict activity of either class of compounds, while presence of EGFR sensitizing mutations, which can be found in significant fractions of NSCLC patients, has been associated with a better outcome in patients receiving EGFR TKIs. Increased EGFR gene copy number could represent a reliable and reproducible tool for proper selection of patients candidate to TKIs or anti-EGFR MAbs. Furthermore, mechanisms of resistance to anti-EGFR strategies are currently being elucidated, allowing identification of subjects who should be excluded from treatment.

In the last decades the epidermal growth factor receptor (EGFR), which is frequently expressed in a variety of epithelial tumors, has been a major target of molecular anticancer therapy.

Activation of the epidermal growth factor receptor (EGFR)-dependent intracellular signaling pathway has a relevant role in the development and the progression of several human cancers. However, EGFR-targeted therapies have a significant clinical activity only in a subgroup of cancer patients whose tumors express the EGFR. This is due in part to the activation of several other signal transduction pathways which will be EGFR-independent and could be responsible for cancer cell growth. A clinically relevant field of research is the development of rational, biologically based multi-targeted therapy combinations which will block cancer cell escape from single target inhibition, such as the use of EGFR inhibitors in monotherapy. A number of clinical trials with EGFR inhibitors in combination with classic cytotoxic agents have been undertaken with both interesting and disappointing results. It is, therefore, felt that combinations of EGFR inhibitors and other novel agents, which is based on the mechanistic knowledge of complementary signaling pathways whose concerted inhibition would efficiently block cancer cell growth, is the rationale therapeutic approach. Some of these pathways [i.e., mammalian target of rapamycin (mTOR), vascular endothelial growth factor receptor (VEGFR), ras/mitogen-activated protein kinase (MAPK) signaling, or insulin like growth factor receptor (IGFR)] which are functionally related to the activity of the EGFR will be discussed in this review to provide a scientific rationale for the combination of drugs which target these pathways with anti-EGFR agents.

The epidermal growth factor receptor (EGFR) signaling plays a key role in tumorigenesis and it has been considered an attractive target for novel antitumoral agents. Small-molecule tyrosine kinase inhibitors such as gefitinib and erlotinib have been approved for the treatment of advanced non-small-cell lung cancer (NSCLC) patients. However, the positive results obtained in early clinical trials with gefitinib were not confirmed in large phase 3 trials, testing the efficacy of this drug in combination with chemotherapy or as single agent. An advantage in overall survival has been observed with erlotinib as single agent in NSCLC, but not in combination with chemotherapy. Conversely, an additive effect has been observed with the combination of the monoclonal antibody cetuximab and irinotecan in heavily pretreated patients with irinotecan-refractory colorectal cancer. The combination of cetuximab and radiotherapy or chemotherapy has also shown efficacy in patients with squamous cancer cell of head and neck. However, the major limit in the development of these agents is the lack of validated predictive markers of response that might allow appropriate selection of patients. In this review, we will discuss the major issues in clinical development of such agents, focusing on the challenges in designing and conducting clinical trials with EGFR inhibitors.