ZD1839: targeting the epidermal growth factor receptor in cancer therapy

The erbB family of receptors, which includes the epidermal growth factor receptor, has been widely implicated in promoting proliferation of malignant cells. The critical role played by epidermal growth factor receptor in cancer has resulted in extensive research for selective inhibitors of the epidermal growth factor receptor signalling pathway. Selective small molecule epidermal growth factor receptor-tyrosine kinase inhibitors, such as ZD1839 (Iressa^?), block signal transduction pathways implicated in proliferation and survival of cancer cells and other host-dependent processes promoting cancer cell growth. In preclinical studies, ZD1839, alone and in combination with other agents, has demonstrated antitumour activity in a range of tumour types. Results from Phase I trials, in healthy volunteers and in patients with advanced disease, have shown that ZD1839 has excellent bioavailability and an acceptable tolerability profile. In these studies, ZD1839 has also shown promising clinical activity in patients with a variety of tumour types. Furthermore, Phase II studies confirmed clinically meaningful antitumour activity and have demonstrated symptom relief in the second- and third-line treatment of non-small cell lung cancer. Phase III trials are currently evaluating ZD1839 in combination with gemcitabine/cisplatin or paclitaxel/carboplatin as first-line treatment of non-small cell lung cancer and an ongoing clinical trial programme is investigating other tumours (i.e., head and neck, prostate, colon and breast) and other combinations. This article provides an overview of the current profile of ZD1839.     

Pharmacokinetics and tolerability of the orally active selective epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in healthy volunteers

OBJECTIVE: To investigate the pharmacokinetics and tolerability of ZD1839 (Iressa), an orally active selective epidermal growth factor receptor-tyrosine kinase inhibitor, in healthy volunteers. DESIGN: Two randomised, double-blind, placebo-controlled, parallel-group studies of pharmacokinetics and tolerability, followed by a nonblind, randomised, 2-period crossover study to assess the effect of food on bioavailability. SETTING: Two centres in the UK. STUDY PARTICIPANTS: Healthy male volunteers aged between 18 and 62 years. INTERVENTIONS: The first study investigated the pharmacokinetics and tolerability of ascending single oral doses of ZD1839 (1 to 75mg). The second study investigated the pharmacokinetics and tolerability of multiple doses of ZD1839 (100mg once daily for 3 days). The third study investigated the effect of food on the bioavailability of a single 50mg dose of ZD1839. OUTCOME MEASURES AND RESULTS: Peak plasma drug concentrations (Cmax) of ZD 1839 occurred between 3 and 7 hours after administration. Cmax and area under the concentration-time curve (AUC) were dose-proportional from 10 to 100mg. The terminal elimination half-life (t1/2beta) was 28 hours (range 12 to 51 hours). Cmax was reduced by 34% and AUC by 14% by ingestion of food; t1/2beta was not affected. Urinary recovery of ZD1839 was <0.5%, indicating that this was not a major route of elimination. The pharmacokinetics of ZD1839 during administration of multiple doses could be predicted from day 1 values. There were no serious adverse events or withdrawals, and the frequency of adverse events was similar that with placebo. CONCLUSIONS: These data support the further clinical investigation of ZD 1839. The elimination half-life suggests that once daily oral administration is appropriate.     

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.     

Phthalocyanine-peptide conjugates for epidermal growth factor receptor targeting

Four phthalocyanine (Pc)-peptide conjugates designed to target the epidermal growth factor receptor (EGFR) were synthesized and evaluated in vitro using four cell lines: human carcinoma A431 and HEp2, human colorectal HT-29, and kidney Vero (negative control) cells. Two peptide ligands for EGFR were investigated: EGFR-L1 and -L2, bearing 6 and 13 amino acid residues, respectively. The peptides and Pc-conjugates were shown to bind to EGFR using both theoretical (Autodock) and experimental (SPR) investigations. The Pc-EGFR-L1 conjugates 5a and 5b efficiently targeted EGFR and were internalized, in part due to their cationic charge, whereas the uncharged Pc-EGFR-L2 conjugates 4b and 6a poorly targeted EGFR maybe due to their low aqueous solubility. All conjugates were nontoxic (IC(50) > 100 μM) to HT-29 cells, both in the dark and upon light activation (1 J/cm(2)). Intravenous (iv) administration of conjugate 5b into nude mice bearing A431 and HT-29 human tumor xenografts resulted in a near-IR fluorescence signal at ca. 700 nm, 24 h after administration. Our studies show that Pc-EGFR-L1 conjugates are promising near-IR fluorescent contrast agents for CRC and potentially other EGFR overexpressing cancers.     

表皮生长因子受体酪氨酸激酶抑制剂在肿瘤治疗中的应用

表皮生长因子受体 (EGFR)酪氨酸激酶 ,是细胞外信号传递到细胞内的重要枢纽 ,它在信号传导、细胞增殖、分化以及各种调节机制中发挥重要作用 ,在多种癌细胞中过度表达。许多研究表明 ,抑制EGFR酪氨酸激酶活性 ,可抑制肿瘤生长。目前 ,已有几种EGFR酪氨酸激酶抑制剂进入了临床试验。本文对几种EGFR酪氨酸激酶小分子抑制剂在肿瘤治疗中的研究进展做一综述。     

Early clinical development of epidermal growth factor receptor targeted therapy in breast cancer

Introduction: Epidermal growth factor receptor (EGFR) targeted treatment has been evaluated but has not shown a clear clinical benefit for breast cancer. This review article aims to consider the knowledge of the biological background of EGFR pathways in dissecting clinical studies of EGFR targeted treatment in breast cancer.

Areas covered: This review focuses on the role of the EGFR pathway and the investigational drugs that target EGFR for breast cancer.

Expert opinion: Recent studies have indicated that EGFR targeted therapy for breast cancer has some promising effects for patients with triple-negative breast cancer, basal-like breast cancer, and inflammatory breast cancer. However, predictive and prognostic biomarkers for EGFR targeted therapy have not been identified. The overexpression or amplification of EGFR itself may not be the true factor of induction of the canonical pathway as an oncogenic driver of breast cancer. Instead, downstream, non-canonical pathways related to EGFR may contribute to some aspects of the biological behavior of breast cancer; therefore, the blockade of the receptor could result in sufficient suppression of downstream pathways to inhibit the aggressive behavior of breast cancer. Mechanistic studies to investigate the dynamic interaction between the EGFR pathway and non-canonical pathways are warranted.     

表皮生长因子受体靶向药物治疗肺部疾病的研究进展

表皮生长因子受体(EGFR)在非小细胞肺癌、黏液高分泌、肺纤维化等一系列肺部疾病中起着重要的作用,为肺部疾病治疗的新靶点.EGFR靶向药物主要有小分子酪氨酸激酶抑制剂(TKI)及抗EGFR单克隆抗体.本文综述目前处于临床研发阶段的新型EGFR靶向药物如不可逆TKI和下游信号通路蛋白抑制剂等,相关药物开发有望解决临床EG...     

人表皮生长因子受体2与肿瘤靶向治疗

人表皮生长因子受体2（human epidermal growth factor receptor 2,Her2）是表皮生长因子受体家族成员之一,在乳腺癌等多种人类肿瘤中过表达,是肿瘤治疗的重要靶点,也是肿瘤诊断和预后检测的重要指标。此文阐述了Her2的结构特征、Her2与肿瘤发生发展的关系、抗Her2单克隆抗体在肿瘤治疗中的应用以及针对Her2靶点的其他治疗策略。     

Targeting epidermal growth factor receptor: Central signaling kinase in lung cancer

Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. Platinum-based doublets remain the current standard therapy for advanced NSCLC. However, overall survival (OS) has reached a plateau, even with the improvement in these regimens. Advances in the knowledge of molecular mechanisms of carcinogenesis have prompted the development of many novel molecular-targeted agents including the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Results of the recent phase III IPASS trial showed that the EGFR-TKI gefitinib has a superior progression-free survival (PFS) to the most commonly used platinum-based doublet carboplatin-paclitaxel as the first-line chemotherapy for pulmonary lung adenocarcinoma among nonsmokers in East Asia. This trial also demonstrated that the presence of EGFR mutation is the best predictor of gefitinib treatment compared with the other biomarkers including EGFR gene copy number. Despite the therapeutic benefit of EGFR-TKIs in NSCLC, most patients eventually develop resistance to these drugs. A secondary mutation of EGFR (T790M) and amplification of MET account for 70% of all cases of acquired resistance to EGFR-TKIs. This review summarizes the significance of EGFR mutations and the mechanisms of resistance to EGFR-TKIs in NSCLC, both of which are critical for patient selection to extend survival as well as to overcome resistance in NSCLC patients treated with EGFR-TKIs.     

表皮生长因子受体家族单克隆抗体耐药机制的研究进展

表皮生长因子受体（EGFR）家族广泛存在于体内各种细胞中,其异常活化与多种人类上皮组织肿瘤的发生、发展密切相关,因此已成为肿瘤治疗的重要靶点之一。目前靶向EGFR家族的药物包括小分子酪氨酸激酶抑制剂和单克隆抗体（简称单抗）类药物,特别是单抗类药物近年来在临床上获得了广泛的应用。但是,越来越多的临床资料表明,大量患者对这类药物表现出原发性耐药或获得性耐药。目前靶向EGFR家族单抗类药物产生耐药的原因主要包括：受体结构改变、血管生成、多种受体酪氨酸激酶的活化、EGFR的亚细胞定位、EGFR下游效应分子的持续激活和EGFR家族生长因子表达的上调等。本文就靶向EGFR家族单抗类药物耐药机制的研究进展进行综述。     

Emerging drugs targeting human epidermal growth factor receptor 2 (HER2) in the treatment of breast cancer

Introduction: Human epidermal growth factor 2 (HER2) overexpression is present in 20% of breast cancer patients. It is associated with more aggressive disease and worse clinical outcome. New drugs are thus needed. Approved and future treatments will be discussed in this review.

Areas covered: The monoclonal antibodies trastuzumab and pertuzumab, the tyrosine kinase inhibitor lapatinib and the antibody-drug conjugate trastuzmab emtansine are approved for HER2 positive breast cancer. The combination of trastuzumab, pertuzumab and docetaxel is currently the first-line treatment in the metastatic setting. New therapies are still needed due to frequent relapse and resistance. These include mammalian target of rapamycin inhibitors, heat shock protein 90 inhibitors, pan-HER2 tyrosine kinase inhibitors, antibody-drug conjugates, immunotherapy agents (antibodies and vaccines), radioimmunotherapy and HER2 specific affinity proteins. Possible developmental issues are the complexity of the molecular biology of the HER2 positive cancer cell, the occurrence of resistance, toxicity and the high cost.

Expert opinion: The determination of the right sequence of use of old and new therapies remains a challenging issue. The selection of patients who do or don’t benefit from potentially toxic chemotherapy is also difficult. Central nervous system metastases are a common problem in HER2 positive breast cancer that needs to be addressed in future trials.     

人表皮生长因子受体3靶向治疗研究进展

人表皮生长因子受体3(human epidermal growth factor receptor 3,Her3/ErbB3)是人表皮生长因子受体家族的一员,能通过配体依赖或非配体依赖的二聚化,激活并调节下游信号通路.目前Her3已成为非小细胞肺癌、乳腺癌等肿瘤治疗非常有潜力的候选靶点.但是,由于缺乏有效的生物标志物,不能针对Her3靶点筛选适应证患者,所以针对Her3的研究存在一定的局限性.此文综述了对Her3靶点的探究以及当前Her3靶向治疗的研究进展.     

Epidermal growth factor receptor targeting

Dr. Jose Baselga (Hospital Vall d'Hebron, Barcelona, Spain) chaired and led a discussion of several posters on the marking and detection of the epidermal growth factor receptor (EGFR), and compounds that target this receptor. The posters consisted of biological studies and phase I trials with EGFR tyrosine kinase (TK) inhibitors. The basis of EGFR targeting in cancer therapy depends on the overexpression in malignancy and potential inhibition with antibodies and TK inhibitors. Correlations have been made between receptor function and inhibition of growth.     

表皮生长因子受体在胰腺癌治疗中的进展

胰腺癌是一种比较常见的消化道恶性肿瘤,传统的化疗和放疗效果均不甚理想。表皮生长因子受体(EGFR)信号转导通路在胰腺癌细胞的发生、增殖、转移、血管形成等方面有重要作用,针对EGFR信号通路的靶向治疗药物已陆续开发和应用。本文就EGFR的结构、功能以及EGFR抑制剂在胰腺癌治疗中的作用予以简要综述。     

Anti-epidermal growth factor receptor drugs in cancer therapy

The epidermal growth factor receptor is a cell membrane growth factor receptor that plays a key role in cancer development and progression. Epidermal growth factor receptor-activated signalling pathways control cell proliferation, apoptosis, angiogenesis and metastatic spread in the majority of human epithelial cancers. Targeting the epidermal growth factor receptor represents a valuable molecular approach to cancer therapy. Promising strategies in clinical development include monoclonal antibodies which block ligand binding and small molecule inhibitors of the tyrosine kinase enzymatic activity which prevent epidermal growth factor receptor autophosphorylation and propagation of downstream intracellular signals. Several anti-epidermal growth factor receptor agents are in clinical development for cancer therapy. Among these, IMC-225 (cetuximab), a chimeric human-mouse monoclonal IgG1 antibody, OSI-774 (Tarceva) and ZD1839 (Iressa), two small molecule epidermal growth factor receptor-selective tyrosine kinase inhibitors, are currently in Phase II and III development as single agents or in combination with conventional therapies, such as radiotherapy or chemotherapy. Results from Phase I - II trials in advanced cancer demonstrate that these drugs have an acceptable tolerability and an interesting clinical activity in patients with a variety of tumour types.     

Anti-epidermal growth factor receptor drugs in cancer therapy

The epidermal growth factor receptor is a cell membrane growth factor receptor that plays a key role in cancer development and progression. Epidermal growth factor receptor-activated signalling pathways control cell proliferation, apoptosis, angiogenesis and metastatic spread in the majority of human epithelial cancers. Targeting the epidermal growth factor receptor represents a valuable molecular approach to cancer therapy. Promising strategies in clinical development include monoclonal antibodies which block ligand binding and small molecule inhibitors of the tyrosine kinase enzymatic activity which prevent epidermal growth factor receptor autophosphorylation and propagation of downstream intracellular signals. Several anti-epidermal growth factor receptor agents are in clinical development for cancer therapy. Among these, IMC-225 (cetuximab), a chimeric human-mouse monoclonal IgG1 antibody, OSI-774 (Tarceva^?) and ZD1839 (Iressa^?), two small molecule epidermal growth factor receptor-selective tyrosine kinase inhibitors, are currently in Phase II and III development as single agents or in combination with conventional therapies, such as radiotherapy or chemotherapy. Results from Phase I – II trials in advanced cancer demonstrate that these drugs have an acceptable tolerability and an interesting clinical activity in patients with a variety of tumour types.     

Targeting epidermal growth factor receptor in the treatment of non-small-cell lung cancer

Importance of the field: The management of non-small-cell lung cancer (NSCLC) has undergone a paradigm shift in the last decade, with the survival advantage demonstrated by the incorporation of anti-epidermal growth factor receptor (EGFR) agents to the standard treatment of advanced/metastatic NSCLC.

Areas covered in this review: We review the existing data regarding the distinct anti-EGFR agents in the NSCLC treatment and the potential role of the investigated biomarkers in the clinical outcome.

What the reader will gain: Tyrosine kinase inhibitors have been used in first-line, second-line and more settings with extremely good results in a subgroup of patients. Cetuximab remains the only anti-EGFR monoclonal antibody to show survival benefit when combined with a cytotoxic agent in the front-line setting. Anti-EGFR treatment is associated with a dramatic clinical benefit in a subgroup of patients, emphasizing the importance of customizing treatment. Several biomarkers have been investigated for their predictive or prognostic value. Validation of identification of biomarkers remains a focus of intense research that may ultimately guide therapeutic decision making, as none of these is considered ideal to discriminate responding from non-responding patients. However, the current evidence of the EGFR mutation analysis from a recent randomised trial suggests that EGFR mutation analysis is quite a good predictive marker for responsiveness to anti-EGFR TKIs. Moreover, the identification of surrogate markers to indicate optimal activity of the anti-EGFR agent is also needed. This review article provides data from large clinical trials using anti-EGFR agents and correlates these results with the tested biomarkers.

Take home message: EGFR inhibition has shown very encouraging results and has improved the outcome of the NSCLC treatment. However, a plateau of significant clinical benefit seems to have been reached and we believe that the time to move away from the traditional treatment approach to more individualizing therapies has come.     

Mutant epidermal growth factor receptors as targets for cancer therapy

The epidermal growth factor (EGF) receptor is overexpressed in many cancers, and is under intensive investigation as a target for cancer therapy. Cancer cells have also been shown to express mutated EGF receptors; these are potentially highly specific targets for cancer therapeutics, as they have not been detected in any normal adult tissues. The most common of these mutant EGF receptors, EGFRvIII, is one in which amino acids 6 - 273 of the extracellular domain are deleted. This specific mutation is common in glioblastoma and in several other types of cancer, and has been shown to promote aggressive growth of tumors in vivo. The loss of part of the extracellular domain results in a receptor that has constitutive tyrosine kinase activity. Current evidence suggests that EGFRvIII has altered signalling properties compared to normal EGF receptor. The mutation in EGFRvIII also creates a new, cancer cell-specific epitope. This epitope is extracellular and therefore represents a very promising target for antibody-directed therapeutics. This review covers our current understanding of the properties of EGFRvIII, and recent developments in the characterization and therapeutic application of EGFRvIII-specific antibodies.     

Possible role of epidermal growth factor receptors in the therapy of pancreatic cancer

Pancreatic cancer is considered an 'orphan' cancer because of its relative low incidence. Unfortunately, even with early diagnosis, mortality rates are high and it ranks eighth in the worldwide ranking of deaths due to cancer. The administration of chemotherapeutic agents for the treatment of advanced disease has failed, and current research focuses on the understanding of molecular pathways in order to investigate the role of targeted therapy. It has been known that the development and the progression of pancreatic cancer are caused by the activation of oncogenes, the inactivation of tumor suppressor genes, and the deregulation of many signaling pathways of various growth factors, among which the epidermal growth factor receptor (EGFR) plays an important role. Growth factor receptors and their ligands not only regulate normal cell processes, but have also been identified as key regulators of human cancer formation. EGFR has been found to be expressed and altered in pancreatic cancer and clearly plays a significant role in tumor development and progression, including cell proliferation, regulation of apoptotic cell death, angiogenesis, and metastatic spread. The amplitude and kinetics of growth factor signaling are determined mainly by a highly regulated endocytic process that sorts and directs activated receptors to degradation in lysosomes. Therefore, EGFR is a legitimate therapeutic target. The aim of this review is to outline the endocytic escape of EGFRs in cancer with special attention towards recent advances in various approaches adopted for EGFR targeting.