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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This review is focused on "new drugs" that might be developed for thyroid cancer treatment. Thyroid cancer is frequently associated to the activation of specific protein (RET, BRAF) and lipid [PI(3)K] kinases. There is good evidence that these genetic lesions are causative events in thyroid cancer initiation or progression. Therefore, novel compounds able to target these kinases might be useful for thyroid cancer treatment. The power of this approach is witnessed by the examples of BCR-ABL, c-KIT and EGFR inhibitors in the treatment of chronic myelogenous leukemia (CML), gastro-intestinal stromal tumors (GIST) and non-small cell lung carcinoma (NSCLC).
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PMID:New drugs in thyroid cancer. 1789 Dec 51

Molecular testing in anatomic pathology is going to become more and more important during the next decade as we develop assays that can aid in diagnosis, prognosis, and predicting response to therapy. The anatomic pathologist needs to be familiar with the different assays available but also needs to be able to discern which are going to become standard of care and which will not. Three different types of tumors are reviewed: thyroid cancer, oligodendroglioma, and lung carcinoma. Molecular assays that are currently in use or on the near horizon, including translocation analyses for RET-PTC and PPARgamma-PAX8, point mutation analysis for BRAF and epidermal growth factor receptor, and genetic loss for 1p and 19q, are discussed.
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PMID:Molecular testing in solid tumors: an overview. 1825 69

Genes of the RAF family, which mediate cellular responses to growth signals, encode kinases that are regulated by RAS and participate in the RAS, RAF, mitogen/extracellular signal-regulated kinase, extracellular signal-regulated kinase and mitogen-activated protein kinase pathway. As BRAF is a serine/threonine kinase that is commonly activated by somatic point mutation, it may provide possible diagnostic and therapeutic targets in human malignant tumors. We analyzed exon 15 of the BRAF gene for mutations in 58 lung, 12 breast, six kidney, 14 cervical, four endometrial and 10 ovarian carcinoma cell lines by PCR-SSCP and direct sequencing. The T1796A transversion was found in one (2.9%) of 34 small cell lung carcinoma and one (8.3%) of 12 breast carcinoma cell lines, resulting in a valine-to-glutamate substitution at residue 599 (V599E). One (4.2%) of 24 non-small cell lung carcinoma cell line showed the C1786G transversion, leading to a leucine-to-valine substitution at residue 596 (L596V). No BRAF point mutations were found in any of the other cell lines examined. Our present results suggest that BRAF may not be a frequent target of mutations involved in the pathogenesis of human lung, breast, kidney, cervical, endometrial and ovarian carcinomas.
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PMID:Mutational analysis of the BRAF gene in human tumor cells. 1839 70

Despite growing evidence that epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation analysis is the most reliable predictor of the lung carcinoma response to EGFR-targeted therapies, there is still discussion about the role of EGFR fluorescence in situ hybridization (FISH). Studies focusing on EGFR FISH as a predictor of response to EGFR-targeted therapies mostly focused on the relationship between EGFR FISH and EGFR mutations. The incidence of KRAS and V-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations in EGFR-amplified or EGFR FISH-positive lung adenocarcinomas remains unknown. The aim of this study was to prospectively characterize the incidence of KRAS and BRAF mutations in EGFR FISH-positive surgically treated lung adenocarcinomas. Of 386 primary lung adenocarcinomas, 77 (20%) were EGFR FISH positive by University of Colorado criteria. The incidence of KRAS mutations in EGFR FISH-positive lung adenocarcinomas was 23% and was not significantly different from the incidence of KRAS mutations in EGFR FISH-negative subsets of adenocarcinoma (32%). A higher mean ratio between EGFR and chromosome 7 enumeration probe (EGFR/CEP7) was observed in EGFR-mutated tumors when compared to cases with KRAS mutation (13 versus 4.5, respectively). Our results showed significant number of EGFR FISH positive/amplified lung adenocarcinomas harboring KRAS mutation. It appears that an increase in EGFR/CEP7 ratio to cutoff point of 4.5 may distinguish between coexisting EGFR (FISH ratio of >5) or KRAS (FISH ratio of 2 to 5) mutations. Observations presented here indicate that the patient selection for EGFR-targeted therapies should include EGFR and KRAS mutational analysis, probably complemented by EGFR FISH studies.
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PMID:EGFR fluorescence in situ hybridization-positive lung adenocarcinoma: incidence of coexisting KRAS and BRAF mutations. 2038 Nov 21

Histone deacetylase (HDAC) inhibitors, such as valproic acid (VPA), constitute a novel class of anticancer agents that cause an increase in acetylated histones and thus restore the expression of dormant tumor-suppressor and other genes related to cell differentiation, cell-cycle arrest or apoptosis of tumor cells. The Ras inhibitor farnesylthiosalicylic acid (FTS, salirasib) attenuates cancer cell proliferation in vitro and in vivo and, under certain circumstances, induces cell death. FTS by itself does not induce differentiation or complete growth arrest. The abovementioned activity of VPA as a differentiation agent suggested that it might be worth investigating its possible therapeutic potential in synergistic combination with FTS. Here, we examined whether the combined application of VPA and FTS could synergistically inhibit the proliferation of cancer cells that express oncogenic K-Ras (A549 nonsmall-cell lung carcinoma cells), DLD1 (colon carcinoma cells) or chronically active wild-type K-Ras and constitutively active B-Raf (ARO, thyroid carcinoma cells). The results showed that combined treatment with VPA and FTS synergistically reduces proliferation in all of these cancer cell lines by downregulating Ras and blocking the expression of Survivin and Aurora A. These alterations, which were most pronounced following the combined treatment, led to a mitotic crisis, as reflected by mislocalization of the chromosomal passenger complex. Our findings thus demonstrate that combination therapy with VPA and FTS might offer a promising therapeutic approach to the treatment of epithelial tumors.
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PMID:Downregulation of survivin and aurora A by histone deacetylase and RAS inhibitors: a new drug combination for cancer therapy. 2047 60

We have investigated the role of individual members of the Raf/Mek/Erk cascade in the onset of K-Ras oncogene-driven non-small cell lung carcinoma (NSCLC). Ablation of Erk1 or Erk2 in K-Ras oncogene-expressing lung cells had no significant effect due to compensatory activities. Yet, elimination of both Erk kinases completely blocked tumor development. Similar results were obtained with Mek kinases. Ablation of B-Raf had no significant effect on tumor development. However, c-Raf expression was absolutely essential for the onset of NSCLC. Interestingly, concomitant elimination of c-Raf and B-Raf in adult mice had no deleterious consequences for normal homeostasis. These results indicate that c-Raf plays a unique role in mediating K-Ras signaling and makes it a suitable target for therapeutic intervention.
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PMID:c-Raf, but not B-Raf, is essential for development of K-Ras oncogene-driven non-small cell lung carcinoma. 2151 45

Matrix metalloprotease-1 (MMP1), a collagenase and activator of the G protein-coupled protease activated receptor-1 (PAR1), is an emerging new target implicated in oncogenesis and metastasis in diverse cancers. However, the functional mouse homologue of MMP1 in cancer models has not yet been clearly defined. We report here that Mmp1a is a functional MMP1 homologue that promotes invasion and metastatic progression of mouse lung cancer and melanoma. LLC1 (Lewis lung carcinoma) and primary mouse melanoma cells harboring active BRAF express high levels of endogenous Mmp1a, which is required for invasion through collagen. Silencing of either Mmp1a or PAR1 suppressed invasive stellate growth of lung cancer cells in three-dimensional matrices. Conversely, ectopic expression of Mmp1a conferred an invasive phenotype in epithelial cells that do not express endogenous Mmp1a. Consistent with Mmp1a acting as a PAR1 agonist in an autocrine loop, inhibition or silencing of PAR1 resulted in a loss of the Mmp1a-driven invasive phenotype. Knockdown of Mmp1a on tumor cells resulted in significantly decreased tumorigenesis, invasion, and metastasis in xenograft models. Together, these data demonstrate that cancer cell-derived Mmp1a acts as a robust functional homologue of MMP1 by conferring protumorigenic and metastatic behavior to cells.
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PMID:Matrix metalloprotease-1a promotes tumorigenesis and metastasis. 2257 25

Lung cancer remains the leading cause of cancer-related mortality in the world despite advances in the field of cancer therapeutics. Traditional treatment with empirically chosen cytotoxic chemotherapeutic agents, have given small, but real survival benefits. Recent advances and insights into molecular pathogenesis of lung cancers have provided some novel molecular targets, offering newer strategies and agents that are tumor specific. Studies have identified mutations in specific genes that are involved in driving the development of lung cancer and so it is important to subsequently target them with specific drugs thus changing paradigms of management of this type of cancer. Recently, Lung Cancer Mutation Consortium (LCMC) has identified at least one of the many recognized "driver mutations" in nearly two thirds of the patients with advanced cancer. This study suggests that identification of driver mutations can help in molecular targeted therapeutics and in addition supplant tumor histology in guiding treatment decisions, identifying subset of patients who may benefit therapy. This review focuses on these mutations identified in specific genes serving as "drivers" of lung tumorigenesis and suggests that clear promise for the future of lung cancer treatment is indeed personalized therapy with drugs chosen according to the patient mutation profile. Most clinically relevant translational advances made in genes involved in lung tumorigenesis namely EML4-ALK fusions, HER2, PIK3CA, AKT, BRAF, MAP2K1, MET mutations and amplifications along with the well established EGFR and KRAS mutations are discussed in the context of NSCLCs. These studies emphasize the need for treatment management based on mutation profile along with routine histology based classification of these tumors in future for a directed therapy and thus a better therapeutic outcome.
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PMID:Targetable "driver" mutations in non small cell lung cancer. 2294 8

The development of tyrosine kinase inhibitor treatments has made it important to test cancer patients for clinically significant gene mutations that influence the benefit of treatment. Targeted next-generation sequencing (NGS) provides a promising method for diagnostic purposes by enabling the simultaneous detection of multiple mutations in various genes in a single test. The aim of our study was to screen EGFR, KRAS, and BRAF mutations by targeted NGS and commonly used real-time polymerase chain reaction (PCR) methods to evaluate the feasibility of targeted NGS for the detection of the mutations. Furthermore, we aimed to identify potential novel mutations by targeted NGS. We analyzed formalin-fixed, paraffin-embedded (FFPE) tumor tissue specimens from 81 non-small cell lung carcinoma patients. We observed a significant concordance (from 96.3 to 100%) of the EGFR, KRAS, and BRAF mutation detection results between targeted NGS and real-time PCR. Moreover, targeted NGS revealed seven nonsynonymous single-nucleotide variations and one insertion-deletion variation in EGFR not detectable by the real-time PCR methods. The potential clinical significance of these variants requires elucidation in future studies. Our results support the use of targeted NGS in the screening of EGFR, KRAS, and BRAF mutations in FFPE tissue material.
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PMID:Comparison of targeted next-generation sequencing (NGS) and real-time PCR in the detection of EGFR, KRAS, and BRAF mutations on formalin-fixed, paraffin-embedded tumor material of non-small cell lung carcinoma-superiority of NGS. 2336 62

The management of non-small cell lung cancer has significantly changed over the past few years through greater understanding of tumour biology. The identification of activating mutations has led to the development of targeted agents. Coexisting mutations in non-small cell lung cancer is uncommon, particularly in squamous cell carcinoma. Our case represents a late gentleman with squamous cell carcinoma of the lung with both a BRAF mutation and ALK rearrangement prior to treatment.
Lung Cancer 2013 Jun
PMID:A rare case of squamous cell carcinoma of the lung harbouring ALK and BRAF activating mutations. 2349 98


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