UMLS:C0149925 - FACTA Search

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Query: UMLS:C0149925 (small cell lung cancer)
6,491 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite recent developments in the diagnosis and conventional treatment of non small cell lung cancer (NSCLC), the prognosis remains unsatisfactory, with 5-year survival rates of approximately 15% for all stages. To date, chemotherapy represents the standard treatment for advanced-non small lung cancer, but efficacy of currently available cytotoxic drugs is modest. Median survival does not exceed 8-10 months. New treatment strategies are needed and considerable hope has been placed in therapies that specifically target the molecular mechanisms of tumour growth. One molecular target of particular relevance to lung cancer pathogenesis is the epidermal growth factor receptor (EGFR), a cell membrane receptor tyrosine kinase. Several inhibitors of EGFR fuctinonal activation have been developed. Amon these, erlotinib (Tarceva) and gefitinib (Iressa) are two orally bioavailable, small molecule EGFR inhibitors of the tyrosine kinase enzymatic activity which prevent EGFR autophosphorylation and activation. In monotherapy, gefitinib and erlotinib have determinated a 10-20% response rate and a 30-50% symptom improvement in previously treated, chemotherapy refractory, advanced NSCLC patients. Furthermore, a randomized, placebo controlled, multicenter phase III study has shown a two months improvement in median survival with erlotinib in the second or third line treatment of metastatic NSCLC patients. We will summarize the clinical evidence on the anticancer activity of small molecule EGFR inhibitors.
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PMID:Small molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in non-small cell lung cancer. 1660 81

Non small cell lung cancer (NSCLC) is a major health public issue because of its frequency and related mortality. Progress with chemotherapy in advanced NSCLC has reached a plateau and more effective and better tolerated therapeutic strategies are needed. Epidermal growth factor receptor (EGFR) is overexpressed in 80% of NSCLC and inhibitors of EGFR tyrosine kinase have now an important place in the management of NSCLC. Most significant results have been obtained with oral inhibitors like erlotinib or gefitinib. Erlotinib role in second and third line setting is firmly established. Recent data suggests that in the first line setting, interesting overall response rates improving survivals can be obtained, in specific subpopulations defined either by histology (adenocarcinomas, adenocarcinomas with bronchioloalveolar features), sex (women), non-smoking status (never-smokers) or biological markers (tumours with EGFR mutations in exons 18-21). Such improvements are especially valuable because inhibitors of EGFR tyrosine kinase are better tolerated than chemotherapy. The exact contribution of monoclonal antibodies like cetuximab is still unclear in NSCLC.
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PMID:[Inhibitors of the EGFR pathway in non small cell lung cancer: what's new in 2007?]. 1723 5

New cancer-specific therapies are based on specific molecular alterations of malignant tumors which are targeted by small inhibitory molecules or specific antibodies. During the development of these agents potential molecular targets are characterized for their expression and importance for pathogenesis and clinical course of the disease. Frequently the assumption is made that the degree of expression of the target protein or the molecular alteration of the target gene allows a prediction if a certain patient will profit from the therapy against this specific protein or not. The first example was that breast cancer patients with overexpression and/or amplification of Her-2 respond to a Her-2-specific antibody (Herceptin) therapy. The expression or activation of the Epidermal Growth Factor Receptor (EGFR, Her-1) are altered in many epithelial tumours and clinical studies indicate that they have important roles in tumor aetiology and progression. Several EGFR-specific monoclonal antibodies and specific tyrosine kinase inhibitors were developed in the last years. Cetuximab is approved for the treatment of metastatic colorectal cancer and advanced squamous cell carcinoma of the head and neck and is investigated in numerous trials for other tumors. The expression of EGFR in the tumor was a prerequisite for the therapy in the first trials, giving the pathologist a central role in treatment decision. However, recent data clearly demonstrate that the degree of EGFR expression does not correlate with therapy response. Therefore a therapy should be not denied to a individual patient solely because of lack of EGFR expression in the tumor. Tyrosine kinase inhibitors (e. g. Gefitinib, Erlotinib) are effective in the treatment of non small cell lung cancer and also investigated in ongoing trials in many cancer types. The correlation of therapy response with both specific molecular alterations (EGFR tyrosine kinase domain mutations) and clinicopathological features (Asian ethnicity, women, non-smokers, bronchioloalveolar differentation) is a good example of the potential role of predictive molecular pathology in the future.
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PMID:[Role of predictive pathology in oncology--example of new therapies targeting EGFR]. 1786 89

ErbBs signalling is always associated with the development of the majority of solid cancers via both the MAPK pathway leading to cell cycle progression and the PI3K pathway causing cell survival. As a consequence, many ErbB antagonists have been developed and patented for cancer treatment purposes. These antagonists belong to two drug classes: monoclonal antibodies (mAbs) and small molecules competing with ATP and inhibiting the tyrosine kinase domain (TKIs). Three patented mAbs are currently approved in clinical cancer treatment: Trastuzumab (Herceptin) directed against HER2 and used to treat breast cancer, Cetuximab and Panitumumab which are anti-EGFR antibodies approved for colorectal cancer treatment. Unfortunately, these mAbs are facing cancer resistance mediated by paracrine activation of other ErbB members or compensatory ErbB signalling factors. In parallel, three TKIs have been approved to treat cancer: Gefitinib (Iressa), Erlotinib (Tarceva) inhibiting specifically EGFR and approved to treat non small cell lung cancer and Lapatinib (Tykerb) which has the dual specificity EGFR/HER2 and recently approved to treat metastatic breast cancer. These TKIs are also facing resistance mutations within the TK domain which increase its affinity to ATP. Resistance problems are leading to the adoption of a new strategy based on the combination of different therapies and this is likely to be the most promising future of cancer treatments.
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PMID:ErbB antagonists patenting: "playing chess with cancer". 1907 65

Receptor Tyrosine Kinases class I (RTK class I, EGF receptor family) constitute a family of transmembrane proteins involved in various aspects of cell growth and survival and have been implicated in the initiation and progression of several types of human malignancies. Activation of EGFR may be because of overexpression, mutations resulting in constitutive activation, or autocrine expression of ligand. In contrast, activation of HER2 occurs mainly by overexpression, which leads to spontaneous homodimerization and activation of downstream signaling events in a ligand-independent manner. EGFR and HER2 have now been validated as a clinically relevant target, and several different types of agents inhibiting these receptors are currently in development. The EGFR inhibitors Erlotinib, Gefitinib, and Cetuximab have undergone extensive clinical testing and have established clinical activity in non small cell lung cancer (NSCLS) and other types of solid tumors. Several of the other erbB inhibitors are also undergoing advanced clinical testing, either alone or in combination with other agents. This review reports various inhibitors, natural, small molecules and monoclonal antibodies, along with their reported activities for various members of erbB family. It will highlight the potential for the development of novel anti-cancer molecules.
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PMID:Receptor tyrosine kinase inhibitors as potent weapons in war against cancers. 1927 41

Vandetanib is a novel, orally available inhibitor of different intracellular signaling pathways involved in tumor growth, progression, and angiogenesis: vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and REarranged during Transfection tyrosine kinase activity. Phase I clinical trials have shown that vandetanib is well tolerated as a single agent at daily doses < or =300 mg. In the phase II setting, negative results were observed with vandetanib in small cell lung cancer, metastatic breast cancer, and multiple myeloma. In contrast, three randomized phase II studies showed that vandetanib prolonged the progression-free survival (PFS) time of patients with non-small cell lung cancer (NSCLC) as a single agent when compared with gefitinib or when added to chemotherapy. Rash, diarrhea, hypertension, fatigue, and asymptomatic QTc prolongation were the most common adverse events. Antitumor activity was also observed in medullary thyroid cancer. Four randomized phase III clinical trials in NSCLC are exploring the efficacy of vandetanib in combination with docetaxel, the Zactima in cOmbination with Docetaxel In non-small cell lung Cancer (ZODIAC) trial, or with pemetrexed, the Zactima Efficacy with Alimta in Lung cancer (ZEAL) trial, or as a single agent, the Zactima Efficacy when Studied versus Tarceva (ZEST) and the Zactima Efficacy trial for NSCLC Patients with History of EGFR-TKI chemo-Resistance (ZEPHYR) trials. Based on a press release by the sponsor of these trials, the PFS time was longer with vandetanib in the ZODIAC and ZEAL trials; the ZEST trial was negative for its primary superiority analysis, but was successful according to a preplanned noninferiority analysis of PFS. Ongoing phase II and III clinical trials will better define the appropriate schedule, the optimal setting of evaluation, and the safety of long-term use of vandetanib.
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PMID:Vandetanib (ZD6474), a dual inhibitor of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) tyrosine kinases: current status and future directions. 1934 11

Non small cell lung cancer (NSCLC) is a lethal disease with poor prognosis. The main percentage of NSCLC patients are diagnosed to have an advanced disease. Standard treatment, such as chemotherapy and radiotherapy, has apparently reached a plateau of effectiveness in improving survival of advanced NSCLC patients. Hence, considerable efforts have started to be made in order to identify novel targets for new biological agents which may safely and effectively be administered to advanced NSCLC patients. Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) and its receptors play an essential role in tumour proliferation. Approaches targeting EGFR and VEGF include monoclonal antibodies (mAbs) and small molecules inhibiting the corresponding receptor-tyrosine kinase activity. Erlotinib is a small molecule inhibitor of EGFR tyrosine-kinase which has brought significant improvements in median survival, quality of life and related symptoms, in an unselected population of advanced NSCLC patients in the second- or third-line setting. Bevacizumab, an anti-VEGF recombinant humanized mAb, is the first targeted agent which, when combined with chemotherapy, reported superior efficacy versus chemotherapy alone in the treatment of advanced NSCLC. ZD6474, a small molecule targeting VEGF tyrosine-kinase activity, showing early evidence of antitumour activity and the excellent toxicity profile, seems to be a promising agent for the treatment of advanced NSCLC. This review shows the latest and the future developments of erlotinib, bevacizumab and ZD6474 in the treatment of advanced NSCLC patients.
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PMID:Recent developments of targeted therapies in the treatment of non-small cell lung cancer. 1951 36

Early studies with tirosine kinase inhibitors (TKI), namely Erlotinib and Gefitinib, in patients with non small cell lung cancer (NSCLC), showed that although most patients did not respond radiologically, a small percentage of those patients (about 10%) had an excellent response to treatment, with radiological regression and clinical response duration. Four patient populations are known as having better response to TKI as opposed to other patients: adenocarcinoma patients, non-smokers, women and asians. Nevertheless, a good general status remains a predictive factor for treatment response. The discovery of the EGFR mutation in NSCLC patients' tumors and its association with clinical response to Erlotinib and Gefitinib, confirmed by a considerable number of retrospective and prospective studies, showed that response rates are between 75-80% in patients carrying this mutation. Although several mutations have been identified, the two commonest (approximately 90%) are located in exons 19 and 21. The authors present two patients studied and treated at the Pulmonology Department's Lung Oncology Unit of CHVNGaia, where Erlotinib was used as 3(rd) line treatment: in one patient, which was part of the population with good response to TKI, a classic exon 19 was identified, and was treated with Erlotinib for twenty months with clinical stability; the other patient did not belong to the above mentioned population and an Exon 20 mutation was identified (a mutation not yet described in literature, being not clear its association with response to treatment with TKI) - treatment was stopped after 7.4months due to disease progression. Rev Port Pneumol 2008; XIV (Supl 3): S43-S51.
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PMID:Treatment of advanced non small cell lung cancer with erlotinib. Two clinical cases. 2596 86

The discovery of Epidermal Growth Factor Receptor (EGFR) mutations in Non Small Cell Lung Cancer (NSCLC) launched the era of personalized medicine in advanced NSCLC, leading to a dramatic shift in the therapeutic landscape of this disease. After ten years from the individuation of activating mutations in the tyrosine kinase domain of the EGFR in NSCLC patients responding to the EGFR tyrosine kinase inhibitor (TKI) Gefitinib, several progresses have been done and first line treatment with EGFR TKIs is a firmly established option in advanced EGFR-mutated NSCLC patients. During the last decade, different EGFR TKIs have been developed and three inhibitors have been approved so far in these selected patients. However, despite great breakthroughs have been made, treatment of these molecularly selected patients poses novel therapeutic challenges, such as emerging of acquired resistance, brain metastases development or the need to translate these treatments in earlier clinical settings, such as adjuvant therapy. The aim of this paper is to provide a comprehensive review of the major progresses reported so far in the EGFR inhibition in this molecularly-selected subgroup of NSCLC patients, from the early successes with first generation EGFR TKIs, Erlotinib and Gefitinib, to the novel irreversible and mutant-selective inhibitors and ultimately the emerging challenges that we, in the next future, are called to deal with.
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PMID:A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives. 2630 62

Epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (non-SCLC) benefits from first-line treatment with first generation tyrosine kinase inhibitors (TKIs). However, drug resistance is inevitable through different mechanisms and is dominated by the acquisition of the T790M mutation within EGFR, which occurs in ~50% of cases. The present study reports the case of a patient originally diagnosed with stage IA lung adenocarcinoma, with a recurrent tumor lesion in each side of the lungs following the surgical removal of the primary tumor. Erlotinib treatment of the recurrent tumors eliminated the tumor on the right side of the lung and resulted in the histological transformation of the tumor on the left side to SCLC following 6 years of treatment. Genetic profiling of the SCLC lesions using targeted next-generation sequencing identified different genetic alterations from the primary tumor, characterized by the newly acquired copy number loss of tumor protein p53 and transcriptional coreceptor 1, and the copy number gain of SRY-box 2. Continuation of treatment with chemotherapy and erlotinib demonstrated moderate disease control for ~1 year prior to the outbreak of a new lung lesion. Liquid biopsy profiling of circulating tumor DNA revealed the acquisition of KRAS proto-oncogene, GTPase (KRAS) p.G12C mutation, indicating the occurrence of another resistance mechanism to erlotinib. During erlotinib treatment, the lung adenocarcinoma progressed through two atypical mechanisms, notably from the transformation to SCLC and the acquisition of the KRAS mutation to surpass EGFR inhibition. However, the combinational and interchanging usage of chemotherapy and TKI resulted in persistent and effective disease control.
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PMID:Transformation to small cell lung cancer and activation of KRAS during long-term erlotinib maintenance in a patient with non-small cell lung cancer: A case report. 3118 38

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