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

Tyrosine kinases have a crucial role as key regulators of signaling pathways that influence cell differentiation and growth. Dysregulation of tyrosine kinase-mediated signaling is understood to be an important oncogenic driver. Genetic rearrangements involving the tyrosine kinase anaplastic lymphoma kinase (ALK) gene occur in non-small cell lung cancer (NSCLC), anaplastic large cell lymphomoas, inflammatory myofibroblastic tumors, and other cancers. Cells with abnormal ALK signaling are sensitive to ALK inhibitors such as crizotinib. This review will highlight the discovery of the fusion between echinoderm microtubule-associated protein-like 4 (EML4) and ALK as an oncogenic driver, recognition of other ALK gene rearrangements in NSCLC, and the confirmation that crizotinib is an effective treatment for patients with ALK-positive NSCLC. Work is underway to further define the role for crizotinib in the treatment of ALK-positive lung cancer and other cancers and to investigate the molecular mechanisms for resistance to ALK inhibition with crizotinib.
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PMID:The potential for crizotinib in non-small cell lung cancer: a perspective review. 2208 42

Lung cancer is one of the most prevalence malignances, of which non-small cell lung cancer (NSCLC) account for 80%-85% of lung cancer. Molecular target therapy is one of the most popular and promising field of NSCLC treatment, and its hotspots includes EGFR (epidermal growth factor receptor), EML4-ALK (echinoderm microtubule associated protein like4-anaplastic lymphoma kinase), etc. Former researches indicated that EML4-ALK fusion and EGFR mutation were excluded mutually. However, cases of patients harbored concomitant EML4-ALK fusion gene and EGFR mutation have been reported continuously at recent. This review aims to summarize the incidence and molecular structure of EML4-ALK fusion gene and EGFR mutation, as well as clinical features of patients with the concomitant genes induced NSCLC.
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PMID:[Research progress in non-small cell lung cancer with concomitant EML4-ALK fusion gene and EGFR gene mutation]. 2210 24

Pulmonary physicians commonly develop relationships with lung cancer patients through the evaluation and staging of the disease prior to the discussion of treatment options with oncologists. Given the relationship that develops, a pulmonologist is often asked about aspects of the treatment plan that may be slightly outside of their comfort zone. The aim of this overview of medical treatment of non-small cell lung cancer is to provide the pulmonologist with an overview of the evidence guiding current practice so that they can be more comfortable answering their patients' questions while awaiting the expert opinion of the oncologist. We discuss standard chemotherapeutic agents, their common side effects, and their use in the adjuvant and neoadjuvant setting, as definitive therapy for locally advanced disease, as palliative therapy for advanced disease, and as maintenance therapy. We also discuss the mechanisms of action and side effects of targeted therapies (including inhibitors of vascular endothelial growth factor [VEGF], epidermal growth factor receptor [EGFR] signaling and the anaplastic lymphoma kinase [ALK] protein), their currently accepted uses, and upcoming phase III trials, the results of which may influence standard practice.
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PMID:Current and emerging medical treatments for non-small cell lung cancer: a primer for pulmonologists. 2211 73

Crizotinib [Xalkori; PF02341066; (R)-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine] is an orally available dual inhibitor of anaplastic lymphoma kinase (ALK) and hepatocyte growth factor receptor. The objectives of the present studies were to characterize: 1) the pharmacokinetic/pharmacodynamic relationship of crizotinib plasma concentrations to the inhibition of ALK phosphorylation in tumors, and 2) the relationship of ALK inhibition to antitumor efficacy in human tumor xenograft models. Crizotinib was orally administered to athymic nu/nu mice implanted with H3122 non-small-cell lung carcinomas or severe combined immunodeficient/beige mice implanted with Karpas299 anaplastic large-cell lymphomas. Plasma concentration-time courses of crizotinib were adequately described by a one-compartment pharmacokinetic model. A pharmacodynamic link model reasonably fit the time courses of ALK inhibition in both H3122 and Karpas299 models with EC(50) values of 233 and 666 ng/ml, respectively. A tumor growth inhibition model also reasonably fit the time course of individual tumor growth curves with EC(50) values of 255 and 875 ng/ml, respectively. Thus, the EC(50) for ALK inhibition approximately corresponded to the EC(50) for tumor growth inhibition in both xenograft models, suggesting that >50% ALK inhibition would be required for significant antitumor efficacy (>50%). Furthermore, based on the observed clinical pharmacokinetic data coupled with the pharmacodynamic parameters obtained from the present nonclinical xenograft mouse model, >70% ALK inhibition was projected in patients with non-small-cell lung cancer who were administered the clinically recommended dosage of crizotinib, twice-daily doses of 250 mg (500 mg/day). The result suggests that crizotinib could sufficiently inhibit ALK phosphorylation for significant antitumor efficacy in patients.
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PMID:Pharmacokinetic/pharmacodynamic modeling of crizotinib for anaplastic lymphoma kinase inhibition and antitumor efficacy in human tumor xenograft mouse models. 2212 95

Non-small-cell lung cancer (NSCLC) has recently been associated with interesting molecular characteristics that have important implications in carcinogenesis and response to targeted therapies. The unsatisfactory treatment outcomes in advanced NSCLC with respect to long-term survival rates may be improved through a better understanding of the molecular etiology of this disease. For instance, several molecular alterations have been defined as "driver mutations," such as mutations in epidermal growth factor receptor (EGFR), Kirsten-rous avian sarcoma (KRAS), and a chromosome 2p inversion producing an EML4-ALK fusion gene (echinoderm microtubule-associated protein-like 4 fused with the anaplastic lymphoma kinase). Other key signaling pathways such as RAS/RAF/MEK, PI3K/AKT/mTOR (mammalian target of rapamycin), mesenchymal-epithelial transition (MET) kinase, LKB1, and insulin-like growth factor 1 (IGF-1) receptor (IGF-1R) have also been identified as novel targets for lung cancer treatment. In this review we focus on the molecular discoveries that have led to the clinical applications and trials of novel targeted agents, including the clinical trials that selectively studied patients who were predicted to achieve the greatest benefit based on the expression of correlative biomarkers.
Clin Lung Cancer 2012 Jul
PMID:Oncogenic pathways, molecularly targeted therapies, and highlighted clinical trials in non-small-cell lung cancer (NSCLC). 2215 78

Although lung cancer remains the leading cancer killer in the United States, recently a number of developments indicate future clinical benefit. These include evidence that computed tomography-based screening decreases lung cancer mortality, the use of stereotactic radiation for early-stage tumors, the development of molecular methods to predict chemotherapy sensitivity, and genome-wide expression and mutation analysis data that have uncovered oncogene "addictions" as important therapeutic targets. Perhaps the most significant advance in the treatment of this challenging disease is the introduction of molecularly targeted therapies, a term that currently includes monoclonal antibodies and small-molecule tyrosine kinase inhibitors. The development of effective targeted therapeutics requires knowledge of the genes and pathways involved and how they relate to the biologic behavior of lung cancer. Drugs targeting the epidermal growth factor receptor, anaplastic lymphoma kinase, and vascular endothelial growth factor are now U.S. Food and Drug Administration approved for the treatment of advanced non-small cell lung cancer. These agents are generally better tolerated than conventional chemotherapy and show dramatic efficacy when their use is coupled with a clear understanding of clinical data, mechanism, patient selection, drug interactions, and toxicities. Integrating genome-wide tumor analysis with drug- and targeted agent-responsive phenotypes will provide a wealth of new possibilities for lung cancer-targeted therapeutics. Ongoing research efforts in these areas as well as a discussion of emerging targeted agents being evaluated in clinical trials are the subjects of this review.
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PMID:Targeted therapies for lung cancer: clinical experience and novel agents. 2215 96

Squamous-cell lung cancer is one of the most prevalent subtypes of lung cancer worldwide and its pathogenesis is closely linked with tobacco exposure. Unfortunately, squamous-cell lung cancer patients do not benefit from major advances in the development of targeted therapeutics such as epidermal growth factor receptor (EGFR) inhibitors or anaplastic lymphoma kinase (ALK) inhibitors that show exquisite activity in lung adenocarcinomas with EGFR mutations or echinoderm microtubule associated protein like-4 (EML4)-ALK fusions, respectively. Major efforts have been launched to characterize the genomes of squamous-cell lung cancers. Among the new results emanating from these efforts are amplifications of the fibroblast growth factor receptor 1 gene and mutations of the discoidin domain receptor 2 gene as potential novel targets for the treatment of squamous-cell lung cancer patients. Here, we provide a review on these discoveries and their implications for clinical trials in squamous-cell lung cancer assessing the value of novel therapeutics addressing these targets.
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PMID:Genetic insight and therapeutic targets in squamous-cell lung cancer. 2226 63

Most anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancers (NSCLCs) are highly responsive to treatment with ALK tyrosine kinase inhibitors (TKIs). However, patients with these cancers invariably relapse, typically within 1 year, because of the development of drug resistance. Herein, we report findings from a series of lung cancer patients (n = 18) with acquired resistance to the ALK TKI crizotinib. In about one-fourth of patients, we identified a diverse array of secondary mutations distributed throughout the ALK TK domain, including new resistance mutations located in the solvent-exposed region of the adenosine triphosphate-binding pocket, as well as amplification of the ALK fusion gene. Next-generation ALK inhibitors, developed to overcome crizotinib resistance, had differing potencies against specific resistance mutations. In addition to secondary ALK mutations and ALK gene amplification, we also identified aberrant activation of other kinases including marked amplification of KIT and increased autophosphorylation of epidermal growth factor receptor in drug-resistant tumors from patients. In a subset of patients, we found evidence of multiple resistance mechanisms developing simultaneously. These results highlight the unique features of TKI resistance in ALK-positive NSCLCs and provide the rationale for pursuing combinatorial therapeutics that are tailored to the precise resistance mechanisms identified in patients who relapse on crizotinib treatment.
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PMID:Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. 2232 27

Increasing understanding of molecular carcinogenesis has begun to change paradigms in oncology. On the diagnostic side, the characterization of key mutations and molecular pathways responsible for tumor development and progression has led to the identification of a large number of potential targets for diagnostic and therapeutic intervention. On the treatment and prevention side, molecular analysis will be of even greater importance for guiding individualized therapy. Diagnostics of molecular lesions present in each tumor will become a key feature of future clinical care. This will allow prediction of response with substantially increased accuracy, stratification of particular patient groups, and eventually personalization of therapy. Striking examples of molecular targeted therapies that have already been established in clinical practice include tyrosine kinase inhibitors in chronic myelogenous leukemia and gastrointestinal stromal tumors, epidermal growth factor receptor (EGFR) inhibition in EGFR-mutated lung cancer, HER2/neu blockade in HER2/neu-positive breast cancer, and anaplastic lymphoma kinase (ALK) inhibitors in lung cancer with EML4-ALK fusion. The scientific development along this line will change the approach to tumor diseases in the future. Patients will be treated according to the specific molecular profiles found in the individual tumor tissue and preferentially with targeted substances, if available.
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PMID:Recent developments and future perspectives of personalized oncology. 2228 81

The implementation of personalized approaches in the treatment of patients with non-small cell lung cancer (NSCLC) requires a precise understanding of tumor biology, a reorientation of clinical development with a strong focus on genetically stratified early phase 'proof of concept' trials, the availability of high-quality 'realtime' genetic diagnostics, and the establishment of networks for molecular screening of lung cancer patients. To achieve this goal, a close interaction between basic researchers, clinical scientists, molecular pathologists, and pharmaceutical companies is essential. We believe that this approach is worth the effort, since personalized therapy in lung cancer has the potential to substantially improve survival in an increasing number of patients. At the moment, established personalized treatment approaches include treatment of patients with NSCLC and activating epidermal growth factor receptor (EGFR) mutations with the EGFR-directed tyrosine kinase inhibitors gefitinib or erlotinib, and treatment of NSCLC patients with genetic aberrations in the anaplastic lymphoma kinase (ALK) oncogene with the mesenchymal-epithelial transition factor (MET)/ALK inhibitor crizotinib. A new approach, the treatment of fibroblast growth factor receptor 1 (FGFR1)-amplified squamous cell lung cancer patients with FGFR inhibitors, is currently being tested in phase I clinical trials.
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PMID:Personalized therapy of lung cancer. 2228 83


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