Pharmacogenetics of EGFR and VEGF inhibition

Even though treatment of several types of solid tumours has improved in the past few years with the introduction of the monoclonal antibodies against epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF), response rates to these targeted therapies are modest. Pharmacogenetic factors have the potential to select patients with higher chance of response to agents that target these pathways. This review provides an overview over germ-line variations in genes that are potentially involved in the pharmacodynamics of the monoclonal antibodies cetuximab, panitumumab and bevacizumab, and which may underlie variable anti-tumour response.     

The strange connection between epidermal growth factor receptor tyrosine kinase inhibitors and dapsone: from rash mitigation to the increase in anti-tumor activity

The presence of an aberrantly activated epidermal growth factor receptor (EGFR) in many epithelial tumors, due to its overexpression, activating mutations, gene amplification and/or overexpression of receptor ligands, represent the fundamental basis underlying the use of EGFR tyrosine kinase inhibitors (EGFR-TKIs). Drugs inhibiting the EGFR have different mechanisms of action; while erlotinib and gefitinib inhibit the intracellular tyrosine kinase, monoclonal antibodies like cetuximab and panitumumab bind the extracellular domain of the EGFR both activating immunomediated anti-cancer effect and inhibiting receptor function. On the other hand, interleukin-8 has tumor promoting as well as neo-angiogenesis enhancing effects and several attempts have been made to inhibit its activity. One of these is based on the use of the old sulfone antibiotic dapsone that has demonstrated several interleukin-8 system inhibiting actions. Erlotinib typically gives a rash that has recently been proven to come out via up-regulated keratinocyte interleukin-8 synthesis with histological features reminiscent of typical neutrophilic dermatoses. In this review, we report experimental evidence that shows the use of dapsone to improve quality of life in erlotinib-treated patients by ameliorating rash as well as short-circuiting a growth-enhancing aspect of erlotinib based on increased interleukin-8 secretion.     

Epidermal growth factor receptor inhibitors in non-small-cell lung cancer

The epidermal growth factor receptor (EGFR) is a cell membrane receptor that plays a key role in cancer development and in the progression of many human malignancies, including non-small-cell lung cancer (NSCLC). EGFR-dependent signaling is involved in cancer cell proliferation, apoptosis, angiogenesis, invasion and metastasis. Targeting the EGFR is a valuable molecular approach in cancer therapy. This receptor is overexpressed in up to 80% of NSCLC cases. Thus, several molecules inhibiting this critical biologic pathway have been synthesized and tested as a single agent or in combination with other anticancer modalities in a wide of clinical trials, including reversible and irreversible small tyrosine kinase inhibitors, such as gefitinib and erlotinib, dual vascular endothelial growth factor receptor EGFR tyrosine kinase inhibitors, such as vandetanib (ZD-6474), and monoclonal antibodies, such as cetuximab, which have shown promising activity in patients with NSCLC. This review focuses on the preclinical and clinical results available with EGFR inhibitors in the treatment of NSCLC patients.     

Antiepidermal growth factor receptor radiosensitizers in rectal cancer

The activation of the epidermal growth factor receptor (EGFR) pathway correlates with a worse prognosis in many solid tumours. Hence, EGFR inhibitors have been developed as a treatment for cancer. The EGFR inhibitor cetuximab has been successfully combined with radical radiotherapy in head and neck cancer. In metastatic colorectal cancer, cetuximab and panitumumab have activity as single agents, and increased response rates are achieved when added to standard chemotherapy schedules. This approach of using EGFR inhibitors has also been extrapolated to the preoperative treatment of locally advanced rectal cancer. Counterintuitively, the combination of chemotherapy, EGFR inhibitors and anti-VEGF antibodies seem to show lower response rates, suggesting antagonism. In rectal cancer, disappointingly low pathological complete response (pCR) rates have often been observed in chemoradiation regimens using EGFR inhibitors. In this study, we aimed to examine the rationale for the integration of EGFR inhibitors into chemoradiation schedules for rectal cancer. We have reviewed the clinical evidence and potential mechanisms for an interaction when EGFR inhibitors are added to fluoropyrimidine-based preoperative chemoradiation, the majority of which have used cetuximab. The primary outcome measure used was pCR. The overall pooled pCR for cetuximab-based chemoradiation was 10.71% (38/356). The rate of G3/G4 gastrointestinal toxicity, in terms of diarrhoea, varied from 5 to 30%, with an overall pooled rate of 13.8% (49/353). A better understanding of the mechanisms involved in combining chemotherapy and radiotherapy might allow more effective future scheduling of biological and chemical agents in combination with radiation.     

Review. EGFR mutations in non-small cell lung cancer--clinical implications

The epidermal growth factor receptor (EGFR) family members seem to play a critical role in lung tumourigenesis and are overexpressed in 40-80% of non-small cell lung carcinoma (NSCLC) tumours. EGFR activation results in a series of downstream signaling events that mediate cancer cell growth, proliferation, motility, adhesion, invasion, apoptosis inhibition and metastasis as well as resistance to chemotherapy. Therefore, EGFR inhibitors seem to be an effective therapy for some patients with previously treated NSCLC. A thorough investigation of EGFR, its major signaling pathways, its identification and biology in NSCLC and the responsiveness to gefitinib, erlotinib and cetuximab in connection to EGFR mutations as well as the possible mechanisms of resistance to tyrosine kinase inhibitors is the scope of this review.     

Epidermal growth factor receptor monoclonal antibodies for the treatment of metastatic colorectal cancer

Treatment of metastatic colorectal disease has evolved over the last decade. Two epidermal growth factor receptor (EGFR) monoclonal antibodies--cetuximab and panitumumab--have been developed in an effort to provide yet another therapeutic option. The EGFR is a transmembrane glycoprotein, expressed constitutively throughout the body and found on many epithelial tissues. The monoclonal antibodies bind to and inhibit the activation of the receptor in the body. This inhibition prevents tumor cell growth, angiogenesis, invasion, and metastasis, and induces apoptosis. Cetuximab and panitumumab exhibit nonlinear pharmacokinetics. Both monoclonal antibodies are approved for the treatment of refractory metastatic colorectal cancer. Cetuximab in combination with irinotecan has significantly better response rates and progression-free survival compared with those of cetuximab or irinotecan alone. Cetuximab and panitumumab as monotherapy have shown significantly better response rates and progression-free survival compared with best supportive care in patients refractory to irinotecan and oxaliplatin. In the Cetuximab Combined with Irinotecan in First Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) trial, treatment-na?ve patients received cetuximab in combination with the chemotherapy regimen infusional leucovorin, fluorouracil, and irinotecan (FOLFIRI) or FOLFIRI alone; the difference in progression-free survival was statistically significant but suggested only a modest benefit over FOLFIRI alone (8.9 vs 8 mo, p=0.036). Results of a preplanned analysis of the first 231 events in the Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) trial favored the control group (chemotherapy regimen with folinic acid [leucovorin], fluorouracil, and oxaliplatin [FOLFOX] plus bevacizumab) instead of the control group plus panitumumab. For clinical consideration, many trials have shown that the intensity or absence of EGFR expression is not a clinically significant predictor of outcomes. Development and intensity of a rash are suggested to be a positive predictor of outcomes in patients. The most common adverse events of EGFR monoclonal antibody therapy are rash, diarrhea, and hypomagnesemia. Other serious but not common adverse events include hypersensitivity reactions and pulmonary toxicity. The availability of EGFR monoclonal antibodies has provided another weapon in the arsenal to treat refractory metastatic colorectal cancer. They have shown safety and efficacy in combination with other chemotherapy regimens and as monotherapy; however, their use as metastatic colorectal cancer therapy needs to be further explored.     

Monoclonal antibodies targeting the epidermal growth factor receptor

The epidermal growth factor receptor (EGFR, HER1) autocrine pathway contributes to a number of highly relevant processes in cancer development and progression, including cell proliferation, regulation of apoptotic cell death, angiogenesis and metastatic spread. The crucial role that EGFR plays in human cancers has led to an extensive search for selective inhibitors of its signaling pathway. The results of a large body of preclinical studies and clinical trials thus far conducted suggest that targeting the EGFR could bring a significant contribution to cancer therapy. A variety of different approaches are currently being used to target the EGFR. The most promising strategies in clinical development include monoclonal antibodies, to prevent ligand binding, and small molecules inhibitors of the tyrosine kinase enzymatic activity, that inhibit autophosphorylation and downstream intracellular signaling. Several blocking monoclonal antibodies against the EGFR have been developed. Among these, IMC-225 is a chimeric human-mouse monoclonal IgG1 antibody that has been the first anti-EGFR targeted therapy to enter clinical evaluation in cancer patients in Phase II and III studies, alone or in combination with conventional radiotherapy and chemotherapy. However, other antibodies against EGFR have demonstrated antitumor activity in several preclinical models of human cancer and are currently under investigation in the clinical setting, such as ICR62, ABX-EGF and EMD72000. This review will focus on all the preclinical data available on monoclonal antibodies engineered against the EGF receptor.     

表皮生长因子受体抑制剂相关性皮肤毒性的研究进展

表皮生长因子受体抑制剂包括小分子酪氨酸激酶抑制剂及单抗类,在肺癌、结直肠癌等肿瘤的分子靶向治疗中起着重要作用。其中小分子酪氨酸激酶抑制剂包括吉非替尼、厄洛替尼、埃克替尼等,单抗类包括西妥昔单抗、帕尼单抗等。以痤疮样皮疹为代表的皮肤毒性是表皮生长因子受体抑制剂使用后最常见的不良反应,严重的皮肤毒性导致药物剂量减少与治疗的中断,影响药物的抗肿瘤疗效。但目前临床对于这一类皮肤毒性仍没有十分有效的处理方法。已有临床试验涉及的处理方法包括口服四环素类药物、局部应用维生素K乳剂、局部应用他克莫司、防晒霜以及表皮生长因子凝胶等。本文综述了此类皮疹的发生机制、治疗皮疹药物的临床试验结果及已有的专家共识或指南,以期为这一类不良反应的处理提供临床思路。     

Emerging EGFR antagonists for breast cancer

Introduction: The EGFR has been associated with the pathogenesis and progression of breast cancer. Treatment based on an EGFR target is emerging as a promising option, especially in combination with conventional therapies. Unfortunately, there are no validated predictor biomarkers, and combinatorial treatments are meeting new resistance.

Areas covered: The purpose of this review is to summarize the existing treatments and the current research based on targeting the EGFR pathway.

Expert opinion: The existing EGFR treatments in breast cancer have shown limited benefit. The combination of the monoclonal antibody cetuximab and platinum salts achieves a 15 – 20% response rate. The effectiveness of tyrosine kinase inhibitors is not completely clear, showing modest or no benefits. Gefitinib treatment has offered some promising results in estrogen receptor + breast cancer. However, it has not been identified as a predictive factor for the appropriate selection of patients. Radioimmunotherapy with anti-EGFR radiolabeled antibodies is a promising strategy in BRCA-mutated breast cancer, but it still requires clinical confirmation. Nevertheless, the crosstalk between pathways frequently leads to treatment resistance. Current research is focused on increasing knowledge about the mechanisms of response and the discovery of predictive markers. Targeting several pathways simultaneously and a correct selection of patients seem essential.     

EGFR-targeting monoclonal antibodies in head and neck cancer

The epidermal growth factor (EGFR) and its receptor were discovered nearly 40 years ago. Over the past decade interruption of this pathway has been exploited in the treatment of various solid tumors. Antibodies that interfere with ligand binding to and dimerization of the EGFR (and small molecules that inhibit the EGFR tyrosine kinase) are anti-proliferative, profoundly radiosensitizing, and synergistic with DNA-damaging cytotoxic agents. Proposed mechanisms of radio- and chemosensitization include enhanced apoptosis, interference with DNA repair and angiogenesis, receptor depletion from the cell surface and antibody-dependent cell-mediated cytotoxicity. This article provides a reader with a comprehensive review of EGFR-targeting antibodies under development for the treatment of head and neck squamous cell cancer (HNSCC) and also summarizes relevant clinical data in this disease with small molecule EGFR inhibitors. One of the monoclonal antibodies, cetuximab, recently received full FDA approval for the treatment of patients with locally advanced (with radiation) or metastatic HNSCC (as a single agent). Regulatory approval followed reporting of a large international study in which the addition of cetuximab to definitive radiation therapy in HNSCC resulted in statistically significant improvements in locoregional control and overall survival. Results of the pivotal trial, other clinical data supporting the regulatory approval, and a preview of the next generation of clinical trials are presented. Considerable work remains to be done, particularly to enhance our understanding of factors that may predict for favorable response to EGFR inhibitor therapy and to evaluate the impact of integrating anti-EGFR therapies into complex chemoradiation programs delivered with curative intent.     

Cetuximab: in the treatment of metastatic colorectal cancer

Cetuximab is a chimeric monoclonal antibody highly selective for the epidermal growth factor receptor (EGFR), which is over-expressed by 25-80% of colorectal cancer tumours and associated with advanced disease. Cetuximab induces a broad range of cellular responses in tumours expressing EGFR, enhancing sensitivity to radiotherapy and chemotherapeutic agents. In a large, randomised, open-label, multicentre study in adult patients with irinotecan-refractory, metastatic colorectal cancer expressing EGFR, cetuximab 400 mg/m2 initial dose followed by 250 mg/m2 weekly plus irinotecan (various doses) produced a greater rate of partial response and disease control (partial response plus stable disease), and increased time to disease progression, compared with cetuximab monotherapy; survival was similar in both groups. The same dosage of cetuximab combined with irinotecan, fluorouracil and folinic acid (various regimens) produced partial responses in 43-58% of patients, a complete response in 5% of patients (one study only) and stable disease in 32-52% of patients with treatment-naive metastatic colorectal cancer expressing EGFR in three small, open-label trials. The most common grade 3/4 adverse events associated with cetuximab monotherapy were acne-like rash, asthenia, abdominal pain and nausea/vomiting. In patients receiving cetuximab plus irinotecan, these were diarrhoea, asthenia, leucopenia and neutropenia.     

Novel substituted quinazolines for potent EGFR tyrosine kinase inhibitors

The type I receptor tyrosine kinases (RTKs) are involved in various aspects of cell growth, survival, and differentiation. Among the known RTKs, the epidermal growth factor receptor (EGFR) and ErbB-2 (HER-2) are two widely studied proteins that are prototypic members of the ErbB family which also includes ErbB-3 (Her-3) and ErbB-4 (Her-4). Overexpression of ErbB-2 and EGFR has been associated with aggressive disease and poor patient prognosis in a range of human tumour types (e.g. breast, lung, ovarian, prostate, and squamous carcinoma of head and neck). Disruption of signal transduction of these kinases has been shown to have an antiproliferative effect. Various approaches have been developed to target the ErbB signalling pathways including monoclonal antibodies (trastuzumab/Herceptin? and cetuximab/Erbitux?) directed against the receptor, and synthetic tyrosine kinase inhibitors (gefitinib/Iressa? and erlotinib/Tarceva?). Since many tumours overexpress ErbB receptors, simultaneous targeting of multiple ErbB receptors therefore becomes a promising approach to cancer treatment. Lapatinib (Tykerb?), a potent dual EGFR/ErbB-2 inhibitor, was approved for the treatment of ErbB-2-positive breast cancer. Despite years of intensive research on EGFR inhibitors, there is a surprising dearth of chemically distinct small inhibitors with a high degree of selectivity. There is also a need for new scaffolds due to the recent finding of EGFR mutations which render the kinase resistant to gefinitib and erlotinib. The structures under study will be quinazolines with different substituents. The structure-activity relationships and biological evaluation of compounds published during the last four years will be reviewed herein.     

EGFR-targeting monoclonal antibodies in head and neck cancer

The epidermal growth factor (EGF) and its receptor were discovered nearly 40 years ago. Over the past decade interruption of this pathway has been exploited in the treatment of various solid tumors. Antibodies that interfere with ligand binding to and dimerization of the EGFR (and small molecules that inhibit the EGFR tyrosine kinase) are anti-proliferative, radiosensitizing, and synergistic with DNA-damaging cytotoxic agents. Proposed mechanisms of radio- and chemosensitization include enhanced apoptosis, interference with DNA repair and angiogenesis, receptor depletion from the cell surface and antibody-dependent cell-mediated cytotoxicity. This article provides the reader with a comprehensive review of EGFR-targeting antibodies under development for the treatment of head and neck squamous cell cancer (HNSCC) and also summarizes relevant clinical data in this disease with small molecule EGFR inhibitors. One of the monoclonal antibodies, cetuximab, recently received full FDA approval for the treatment of patients with locoregionally advanced (with radiation) or metastatic HNSCC (as a single agent). Regulatory approval followed reporting of a large international study in which the addition of cetuximab to definitive radiation therapy in HNSCC resulted in statistically significant improvements in locoregional control and overall survival. Results of the pivotal trial, other clinical data supporting the regulatory approval, and a preview of the next generation of clinical trials are presented. Considerable work remains to be done, particularly to enhance our understanding of factors that may predict for favorable response to EGFR inhibitor therapy and to evaluate the impact of integrating anti-EGFR therapies into complex chemoradiation programs delivered with curative intent.     

Targeted therapy in colorectal cancer: current status and future challenges

Treatment of metastatic colorectal cancer (mCRC) has progressed significantly over the last years, particularly with the introduction of targeted therapies. Two groups of agents targeting either the epidermal growth factor receptor (EGFR) or the vascular endothelial growth factor (VEGF) have been integrated into clinical practice. Currently available agents with established role include the anti-EGFR monoclonal antibodies (mAbs) cetuximab / panitumumab and the anti-VEGF mAb bevacizumab. This review presents an update on the clinical studies evaluating the role of anti-EGFR and anti-VEGF agents in mCRC. Moreover, we provide current data regarding the mechanism of action and pathways mediating resistance to these agents. In addition, we present recent data with respect to biomarkers and we discuss future therapeutic strategies.     

Production, novel assay development and clinical applications of monoclonal antibodies

Since the advent of hybridoma technology 35 years ago, research on monoclonal antibodies has developed enormously. Monoclonal antibodies of mouse origin were the first to be produced and continue to be the most popular affinity reagents for investigating the proteome of all organisms. For their adaptability to a variety of biological assays monoclonal antibodies are key tools for basic research as well as for diagnosis and therapy of human diseases. Recently, the expanding demand of high-quality antibodies with better specificities has resulted in a significant improvement in traditional hybridoma production methods. Owing to the ability of these affinity reagents to selectively target tumour cells, cancer has been a major focus of programmes for monoclonal antibody development. This review focuses on patents related to the advances made in the monoclonal antibody manufacture, showing how the traditional production techniques were turned into alternative, faster and more effective methods. Other patents are focussed on new technologies in which monoclonal antibodies are employed for the development of high-performance screening assays. A conclusive series of patents is related to monoclonal antibodies which find application to the diagnosis and the treatment of specific cancer diseases such as haematological malignancies and solid tumours.     

Panitumumab the first fully human monoclonal antibody: from the bench to the clinic

Panitumumab (formerly known as ABX-EGF) is the first fully human monoclonal antibody to epidermal growth factor receptor to enter clinical trials for the treatment of solid tumors. Like cetuximab (Erbitux; BMS), it is directed against the extracellular ligand-binding domain of the receptor and results in blockade of the essential downstream signaling pathways that are known to govern apoptosis, proliferation and differentiation of both normal and neoplastic cell types in a wide array of tissues. It has a very high affinity for epidermal growth factor receptor and has been generally well tolerated and associated with very few infusion reactions. As a fully human agent, panitumumab has not been associated with the formation of any antibodies directed against it that has been evidenced by a very reliable pharmacokinetic profile with possible dosing schedules ranging from 1 to 3 weeks. Similar to other agents targeting the epidermal growth factor receptor pathway, a rash has been the primary toxicity and is dose dependent up to 2.5 mg/kg at which dose 100% of all patients have been affected. The anti-tumor activity of panitumumab has been tested in vitro and in vivo, and inhibition of tumor growth has been observed in numerous cancer models, particularly lung, kidney and colorectal. It has been efficacious and well tolerated both as monotherapy and in combination with other chemotherapeutic agents. Several phase I trials, two phase II trials and most recently a phase III trial in pretreated colorectal cancer have been carried out to date. Currently, there is also a randomized phase III trial (Panitumumab Advanced Colorectal Cancer Evaluation Study) investigating the role of panitumumab in the first-line treatment of colorectal cancer. No unfavorable drug-drug interactions have been observed nor has there been any effect on the pharmacokinetics of drugs with which it is being used. Recent progress in preclinical and clinical studies of panitumumab is reviewed.     

西妥昔单抗联合NK-DC在肿瘤治疗中的研究进展

目的西妥昔单抗作为一种EGFR的单克隆抗体已广泛应用于结直肠癌、头颈部肿瘤等癌症的治疗中。最近的研究证明其对肿瘤免疫起着重要的作用,尤其是对NK和DC细胞的影响,及对NK介导的ADCC作用。本文总结了西妥昔单抗的抗肿瘤作用,及其对NK-DC的抗肿瘤作用的影响,以便未来对肿瘤过继性免疫治疗提供方案。     

Rationale and clinical validation of epidermal growth factor receptor as a target in the treatment of head and neck cancer

Recurrent/metastatic head and neck cancer is an area of high, unmet treatment need. There is a strong rationale for targeting the epidermal growth factor receptor (EGFR) in head and neck cancer as most of these tumors express high levels of EGFR relative to normal tissue, with high expression correlating with poor patient outcome. This rationale has been validated in extensive preclinical studies. Two small molecules with EGFR inhibitory activity, gefitinib ('Iressa', ZD1839) and erlotinib ('Tarceva', OSI-774), and a humanized monoclonal antibody against the EGFR extracellular domain, cetuximab ('Erbitux', C225), are in clinical trials for advanced head and neck cancer. The initial results of these trials are promising. Gefitinib and erlotinib show activity as monotherapy in patients with recurrent or metastatic head and neck cancer, and have an acceptable safety profile compared with conventional chemotherapy. Gefitinib, which can be given at doses below the maximum tolerated dose, is associated with slightly lower rates of adverse events than erlotinib, which is dosed at the maximum tolerated dose. Combinations of cetuximab with radiotherapy or platinum-based chemotherapy have also shown activity in phase I/II studies. Both gefitinib and cetuximab have entered phase III studies. The results of these trials, which will mature over the next few years, will help determine the optimal use of EGFR agents in head and neck cancers.     

Antitumor therapeutic strategies based on the targeting of epidermal growth factor-induced survival pathways

Cellular receptors for the Epidermal Growth Factor are considered important targets for the experimental treatment of human cancer. Monoclonal antibodies as well as small tyrosine kinase inhibitors have been developed and have undergone extensive evaluation in preclinical and clinical studies. Most of these studies have been conceived on the general idea that epidermal growth factor receptor (EGFR) plays a critical role on the growth and survival of human tumors. This assumption has been derived by the successful development of BCR/ABL tyrosine kinase inhibitors in human chronic myeloid leukemia as well as on the activity of antiCD20 monoclonal antibodies in lymphoproliferative disease and of anti HER2 agents in breast tumors overexpressing the targeted antigens. It is now becoming clear that factors regulating sensitivity to kinase inhibitors may differ from monoclonal antibodies and that the molecules targeted by interferring drugs must be prioritaire for growth and survival of those specific tumors in order to achieve valuable results. Recent evidence of major responses to the EGFR inhibitor Gefitinib in tumors harboring activating mutations in the EGFR appears on line with this concept. In this article we will discuss the significance of targeting the EGFR driven survival pathways. Specifically, we will afford the point of EGFR survival signalling prioritization by means of pharmacological treatment. Finally, we will address the role of profiling technologies and of novel computational system biology-based approaches for identification of innovative strategies for effective targeting of EGFR driven survival pathways.