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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activation of the epidermal growth factor receptor (EGFR) has been linked to tumour proliferation, invasion, metastasis and angiogenesis in epithelial tumours. Inhibitors of the EGFR have emerged as promising anticancer agents and two main approaches have been developed, humanised monoclonal antibodies and tyrosine kinase inhibitors. This review discusses the current status of EGFR tyrosine kinase inhibitors (EGFR-TKIs) that have entered clinical development. EGFR-TKIs are generally well tolerated and can sometimes produce impressive tumour regression in patients with advanced non-small-cell lung cancer. However, highly predictive or surrogate markers of activity have not been identified and there remains a need for translational research in their future development.
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PMID:Epidermal growth factor receptor tyrosine kinase inhibitors. 1515 May 74

Cytotoxic chemotherapy has only yielded modest gains in survival in lung cancer in the past decade. However, the development of agents targeting specific signaling pathways that drive carcinogenesis has heralded a major paradigm shift in the approach to treatment of cancer. In non-small cell lung cancer (NSCLC), many researchers have focused on the epidermal growth factor receptor (EGFR) because this protein is present on a relatively high proportion of non-small cell lung cancers and its intracellular tyrosine kinase activates a signaling cascade that drives tumor growth. Blockade of the EGFR by small molecule inhibitors of the tyrosine kinase, such as gefitinib and erlotinib, causes tumor regressions in NSCLC. Phase II monotherapy trials of EGFR tyrosine kinase inhibitors in patients with previously treated advanced NSCLC demonstrated anti-tumor activity with objective response rates of 10-19% with acceptable toxicities and an associated improvement in lung cancer symptomatology. Gefitinib is now an FDA approved treatment for advanced NSCLC previously treated with platinum and docetaxel-based therapies. However, phase III trials of gefitinib and erlotinib in combination with chemotherapy doublets have failed to demonstrate a survival advantage when compared with chemotherapy alone. It remains unclear why these drugs work so effectively in certain patients and so poorly in combination with chemotherapy. The goal of ongoing and future investigation is to identify which patients may benefit from this new therapeutic approach.
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PMID:Targeting non-small cell lung cancer with epidermal growth factor tyrosine kinase inhibitors: where do we stand, where do we go. 1518 24

Gefitinib ('Iressa', ZD1839) is an orally active epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has demonstrated antitumour activity and favourable tolerability in Phase II studies. We investigated whether EGFR expression levels could predict for response to gefitinib in patients with advanced non-small-cell lung cancer (NSCLC), who received gefitinib (250 mg day(-1)) as part of a worldwide compassionate-use programme. Tissue samples were analysed by immunohistochemistry to assess membrane EGFR immunoreactivity. Of 147 patients enrolled in our institution, 50 patients were evaluable for assessment of both clinical response and EGFR expression. The objective tumour response rate was 10% and disease control was achieved in 50% of patients. Although high EGFR expression was more common in squamous-cell carcinomas than adenocarcinomas, all objective responses were observed in patients with adenocarcinoma. Response and disease control with gefitinib were not associated with high EGFR expression. Overall, median survival was 4 months, and the 1-year survival rate was 18%. Strong EGFR staining correlated with shorter survival time for all patients. Gefitinib demonstrated promising clinical activity in this group of patients with NSCLC. These results have also shown that EGFR expression is not a significant predictive factor for response to gefitinib.
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PMID:Analysis of epidermal growth factor receptor expression as a predictive factor for response to gefitinib ('Iressa', ZD1839) in non-small-cell lung cancer. 1518 94

Patients with advanced non-small cell lung cancer (NSCLC) who fail to respond to cytotoxic chemotherapy or who cannot tolerate chemotherapy have limited treatment options. In addition, patients with advanced NSCLC often experience disease-related symptoms that impact their quality of life. Treatment goals in this setting include palliation of symptoms and improvement in quality of life, in addition to tumor response or disease stabilization and increased survival. ZD1839 (Iressa, gefitinib) is an orally active, small-molecule, epidermal growth factor receptor-tyrosine kinase inhibitor that has shown single-agent efficacy for previously treated advanced NSCLC. In phase I clinical trials, ZD1839 provided relief from symptoms often associated with lung cancer, including fatigue, shortness of breath, and chest pain. The IRESSA Dose Evaluation in Advanced Lung Cancer (IDEAL)-1 and IDEAL-2 clinical trials evaluated ZD1839 treatment at 250 mg/day and 500 mg/day in patients with advanced NSCLC for objective tumor response and safety, as well as for improvements in NSCLC-related symptoms and health-related quality of life. The majority of patients enrolled in these studies had received multiple prior treatments. Rapid, sustained symptom improvement was documented for many patients receiving ZD1839 at 250 mg/day or 500 mg/day in both IDEAL trials and was positively associated with clinical benefits, such as tumor response and increased survival.
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PMID:Effects of ZD1839 (Iressa, gefitinib) treatment on symptoms and quality of life in patients with advanced non-small cell lung cancer. 1520 79

Gefitinib (Iressa) is a novel targeted therapy that inhibits the tyrosine kinase activity of the epidermal growth factor receptor by competitively blocking the ATP binding site. In preclinical studies gefitinib has shown potent activity in a number of tumor models, including several lung cancer cell lines and xenografts. Two large randomized Phase II studies (IDEAL 1 and IDEAL 2) in pretreated non-small cell lung cancer reported a response rate approaching 20% in second-line patients and approximately 10% in those pretreated with two or more chemotherapy regimens. The median survival in these two studies approached 6-8 months. As a first-line therapy, gefitinib has been assessed in combination with two different chemotherapy regimens in two large randomized studies (INTACT 1 and INTACT 2). Both studies failed to show an improvement in survival on a total patient accrual of >1000 patients in each study. Other end points (e.g., time to progression and response rate) were also not improved by the addition of gefitinib. Additional studies are indicated to assess the possible role of gefitinib in the maintenance of patients who received chemotherapy or chemoradiotherapy. Studies investigating gefitinib as first-line monotherapy are also required.
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PMID:The role of gefitinib in lung cancer treatment. 1521 64

Large, randomized trials have been conducted in the primary prevention of lung cancer using micronutrients or derivative agents for which epidemiological data suggested a potential role in lung cancer prevention. The disappointing primary prevention trials of beta-carotene, alpha-tocopherol, and retinyl palmitate have led to the development of a more compact, biomarker-driven series of translational trials of lung cancer prevention that target reversal of premalignancy as the primary end point. Serial trials of 13-cis-retinoic acid (isotretinoin) and other retinoids have failed to show a difference in reversal of premalignancy in active smokers or in second primary tumor prevention. However, a trial of 9-cis-retinoic acid, a pan retinoid/rexinoid agonist, showed up-regulation of retinoic acid receptor beta (RAR-beta), a potentially important intermediate marker of response in lung cancer premalignancy. Other planned or ongoing trials currently target important molecular markers of lung carcinogenesis and progression including cyclooxygenase-2, the ras-signaling pathway through farnesyl transferase inhibitors, and the tyrosine kinase/epidermal growth factor receptor pathway (gefitinib, erlotinib). Early results of bioadjuvant trials in head and neck cancer suggest that combination chemoprevention will ultimately be an important option.
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PMID:Molecularly targeted approaches to the chemoprevention of lung cancer. 1521 68

The epidermal growth factor receptor (EGFR) is a member of the erbB family of tyrosine kinase receptors (RTK). The EGFR is involved in cell proliferation, metastasis and angiogenesis, and is expressed in a large proportion of epithelial tumours. The two main classes of EGFR inhibitors in clinical trials are the RTK inhibitors and the monoclonal antibodies. The clinical development of EGFR inhibitors has introduced new challenges to the design of phase I, II, and III trials. Both classes of agents can be safely administered at doses sufficient to inhibit the EGFR system. Receptor tyrosine kinase inhibitors have been extensively evaluated in non-small-cell lung cancer. In this setting, gefitinib has demonstrated activity in patients who fail initial chemotherapy. Monoclonal antibodies have been developed in combination with cytotoxic chemotherapy in several tumour types, most notably colorectal and head and neck cancer. The preliminary results suggest an increase in response rate and time to progression with the combination of cetuximab and chemotherapy in both disease models. Future issues in the development of EGFR inhibitors include the identification of biologic predictors of response, combination with other targeted agents, and their utilisation in earlier stage malignancies.
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PMID:Targeting the epidermal growth factor receptor. 1523 78

It is now known that vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) are autocrine growth factors in malignant mesothelioma; epidermal growth factor receptor (EGFR) is also highly overexpressed. Cytotoxic drugs that target these growth factors offer fresh potential for the treatment of mesothelioma. Clinical trials have recently been initiated to evaluate the anti-tumour activity of the VEGF inhibitors SU5416, bevacizumab and thalidomide. ZD1839 (Iressa, AstraZeneca), an inhibitor of EGFR tyrosine kinase, is also being evaluated. Two clinical trials are planned to evaluate the two PDGF inhibitors Gleevec (Imatinib mesylate, STI-571, Novartis Pharmaceuticals) and PTK787 (Novartis Pharmaceuticals).
Lung Cancer 2004 Aug
PMID:Moving beyond chemotherapy: novel cytostatic agents for malignant mesothelioma. 1526 45

Non-small cell lung cancer (NSCLC) remains the most common cause of cancer-related death in the developed world. Despite advances in therapy with conventional modalities, over 85% of patients will die from their disease within 5 years of diagnosis. For patients with inoperable lung cancer, the addition of chemotherapy to radical radiotherapy yields a small but significant 10% survival benefit at 3 years. However, the systemic toxicity of chemotherapy is common and may be severe. Over the past 20 years, dramatic improvements in our understanding of the molecular etiology of cancer have enabled the development of novel targeted therapies. Overexpression of the epidermal growth factor receptor (EGFR) in lung cancer correlates with an aggressive disease course and poor tumor response to radiotherapy. Strategies to inhibit this molecular switch have become a focus for drug development. Preclinical efficacy has been repeatedly demonstrated with anti-EGFR monoclonal antibodies and small molecule tyrosine kinase inhibitors, and responses have been documented in the clinic with acceptable toxicity. Phase III trials combining EGFR tyrosine kinase inhibitors with radical chemoradiation are recruiting at present. This review addresses the current challenges of discovering how best to use these new anticancer therapies, with particular emphasis on the enhancement of existing therapeutic strategies such as radical radiotherapy, factors relating to patient selection and prediction of clinical response.
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PMID:Combination epidermal growth factor receptor inhibition and radical radiotherapy for NSCLC. 1527 Jun 61

Molecular inhibition of epidermal growth factor receptor (EGFR/HER1) signaling is under active investigation as a promising cancer treatment strategy. We examined the potency of EGFR inhibition achieved by combining anti-EGFR monoclonal antibody and tyrosine kinase inhibitor, which target extracellular and intracellular domains of the receptor, respectively. We specifically studied the combination of cetuximab (Erbitux, C225; ImClone Systems, New York, NY) with either gefitinib (Iressa, ZD1839; AstraZeneca, Macclesfield, UK) or erlotinib (Tarceva, OSI-774; Genentech, South San Francisco, CA) across a variety of human cancer cells. The combination of cetuximab plus gefitinib or erlotinib enhanced growth inhibition over that observed with either agent alone. As measured by immunostaining, inhibition of EGFR phosphorylation with the combination of cetuximab plus gefitinib or erlotinib was augmented over that obtained with single-agent therapy in head and neck (H&N) cancer cell lines. Phosphorylation inhibition of downstream effector molecules [mitogen-activated protein kinase (MAPK) and AKT] also was enhanced in tumor cells treated with the combination of cetuximab plus gefitinib or erlotinib. Flow cytometry and immunoblot analysis demonstrated that treatment of H&N tumor cells with cetuximab in combination with either gefitinib or erlotinib amplified the induction of apoptosis. Following establishment of cetuximab-resistant cell lines, we observed that gefitinib or erlotinib retained the capacity to inhibit growth of lung and H&N tumor cells that were highly resistant to cetuximab. Treatment with gefitinib or erlotinib, but not cetuximab, also could further inhibit the activation of downstream effectors of EGFR signaling in cetuximab-resistant cells, including MAPK and AKT. These data suggest that tyrosine kinase inhibitors may further modulate intracellular signaling that is not fully blocked by extracellular anti-EGFR antibody treatment. Finally, animal studies confirmed that single EGFR inhibitor treatment resulted in partial and transient tumor regression in human lung cancer xenografts. In contrast, more profound tumor regression and regrowth delay were observed in mice treated with the combination of cetuximab and gefitinib or erlotinib. Immunohistochemical staining, which demonstrated significant reduction of the proliferative marker proliferating cell nuclear antigen in mice treated with dual EGFR inhibitors, further supported this in vivo observation. Together, these data suggest that combined treatment with distinct EGFR inhibitory agents can augment the potency of EGFR signaling inhibition. This approach suggests potential new strategies to maximize effective target inhibition, which may improve the therapeutic ratio for anti-EGFR-targeted therapies in developing clinical trials.
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PMID:Dual-agent molecular targeting of the epidermal growth factor receptor (EGFR): combining anti-EGFR antibody with tyrosine kinase inhibitor. 1528 42


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