Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

About ten years ago, docetaxel was established as a second-line chemotherapy for advanced non-small cell lung cancer(NSCLC). After that, pemetrexed has been shown to be similar to docetaxel in response rate, overall survival and progression-free survival, and to have a more favorable toxicity profile. As a result, pemetrexed was approved in the US and Europe. On the other hand, EGFR TKI has been compared to docetaxel or best supportive care in phase III trials. Based on these results, EGFR-TKI is now considered one of the treatment options in a second-line setting for NSCLC. Recently, it has been shown that EGFR-TKIs are very effective against EGFR mutation-positive NSCLC in many reports. Thus, EGFR-TKIs are examined as first-line chemotherapy against those patients. Since, other molecular- targeted drugs except for EGFR-TKI have been developed, we hope for the establishment of further effective second- line treatment for NSCLC. As for small cell lung cancer, phase III trials for second-line treatment are few. Topotecan is the only agent which has been proved to show a significant prolongation of survival for the best supportive care. In Japan, amrubicin is considered an effective agent for relapsed small cell lung cancer. We hope to reveal the efficacy of amrubicin in randomized phase III trials.
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PMID:[Second-line treatment and targeted therapy of advanced lung cancer]. 1946 Nov 68

Lung cancer is the commonest cancer killer. Small cell lung cancer (SCLC) is initially chemosensitive, but rapidly relapses in a chemoresistant form with an overall survival of <5%. Consequently, novel therapies are urgently required and will likely arise from an improved understanding of the disease biology. Our previous work showed that fibroblast growth factor-2 induces proliferation and chemoresistance in SCLC cells. Here, we show that the selective fibroblast growth factor receptor (FGFR) inhibitor PD173074 blocks H-510 and H-69 SCLC proliferation and clonogenic growth in a dose-dependent fashion and prevents FGF-2-induced chemoresistance. These effects correlate with the inhibition of both FGFR1 and FGFR2 transphosphorylation. We then determined the efficacy of daily oral administration of PD173074 for 28 days in two human SCLC models. In the H-510 xenograft, tumor growth was impaired similar to that seen with single-agent cisplatin administration, increasing median survival compared with control sham-treated animals. Crucially, the effect of cisplatin was significantly potentiated by coadministration of PD173074. More dramatically, in H-69 xenografts, PD173074 induced complete responses lasting >6 months in 50% of mice. These effects were not a consequence of disrupted tumor vasculature but instead correlated with increased apoptosis (caspase 3 and cytokeratin 18 cleavage) in excised tumors. Moreover, in vivo imaging with 3'-deoxy-3'-[(18)F]fluorothymidine-positron emission tomography ([(18)F]FLT-PET) showed decreased intratumoral proliferation in live animals treated with the compound at 7 to 14 days. Our results suggest that clinical trials of FGFR inhibitors should be undertaken in patients with SCLC and that [(18)F]FLT-PET imaging could provide early in vivo evidence of response.
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PMID:The fibroblast growth factor receptor inhibitor PD173074 blocks small cell lung cancer growth in vitro and in vivo. 1990 55

The year 2009 has lead to new data clearly impacting therapeutic management strategies in NSCLC. Personalized medicine is becoming a reality for patients with EGFR mutation as well as for the recruitment of patients in certain clinical trials (EML4-ALK translocation, KRAS mutation...). Maintenance trials are based on questionable statistical designs but this approach may have an interest in certain subset of patients. Little improvements are being achieved in SCLC and locally advanced NSCLC.
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PMID:[Lung cancer: an update in 2010]. 2002 51

While chemotherapy provides useful palliation, advanced lung cancer remains incurable since those tumors that are initially sensitive to therapy rapidly develop acquired resistance. Resistance may arise from impaired drug delivery, extracellular factors, decreased drug uptake into tumor cells, increased drug efflux, drug inactivation by detoxifying factors, decreased drug activation or binding to target, altered target, increased damage repair, tolerance of damage, decreased proapoptotic factors, increased antiapoptotic factors, or altered cell cycling or transcription factors. Factors for which there is now substantial clinical evidence of a link to small cell lung cancer (SCLC) resistance to chemotherapy include MRP (for platinum-based combination chemotherapy) and MDR1/P-gp (for non-platinum agents). SPECT MIBI and Tc-TF scanning appears to predict chemotherapy benefit in SCLC. In non-small cell lung cancer (NSCLC), the strongest clinical evidence is for taxane resistance with elevated expression or mutation of class III beta-tubulin (and possibly alpha tubulin), platinum resistance and expression of ERCC1 or BCRP, gemcitabine resistance and RRM1 expression, and resistance to several agents and COX-2 expression (although COX-2 inhibitors have had minimal impact on drug efficacy clinically). Tumors expressing high BRCA1 may have increased resistance to platinums but increased sensitivity to taxanes. Limited early clinical data suggest that chemotherapy resistance in NSCLC may also be increased with decreased expression of cyclin B1 or of Eg5, or with increased expression of ICAM, matrilysin, osteopontin, DDH, survivin, PCDGF, caveolin-1, p21WAF1/CIP1, or 14-3-3sigma, and that IGF-1R inhibitors may increase efficacy of chemotherapy, particularly in squamous cell carcinomas. Equivocal data (with some positive studies but other negative studies) suggest that NSCLC tumors with some EGFR mutations may have increased sensitivity to chemotherapy, while K-ras mutations and expression of GST-pi, RB or p27kip1 may possibly confer resistance. While limited clinical data suggest that p53 mutations are associated with resistance to platinum-based therapies in NSCLC, data on p53 IHC positivity are equivocal. To date, resistance-modulating strategies have generally not proven clinically useful in lung cancer, although small randomized trials suggest a modest benefit of verapamil and related agents in NSCLC.
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PMID:Tumor and host factors that may limit efficacy of chemotherapy in non-small cell and small cell lung cancer. 2004 43

Mutations of some contributing factors (p53, p16, Rb, and EGFR) are believed to affect diagnosis and drug resistance of lung cancer. We evaluated the efficacy of a multimarker panel for molecular diagnosis of lung cancer, using a high-throughput suspension microarray. One hundred and twenty-five lung cancer specimens and 30 tumor-free lung tissue samples were assayed by multiplex polymerase chain reaction with specific probes designed to detect hot-spot mutations in p53, p16, Rb, and EGFR. The mutation rates of p53, p16, Rb, or EGFR in the lung cancer specimens were 36.8, 15.2, 11.2, and 18.4%, respectively. Inclusion of four markers elevated sensitivity to 68.0%. The specificity and accuracy of four-marker detection were 90.0 and 72.3%, and the mutation rates of this panel in stage I, stage II and stage III disease were 62.2, 65.9 and 75.0%, respectively. Mutation at p16 occurred more frequently in non-small cell lung cancer (19.3%) than in small cell lung cancer (5.4%); while the mutation rate of Rb was 32.4% in small cell lung cancer versus 2.3% in non-small cell lung cancer. We conclude that simultaneous detection of p53, Rb, p16, and EGFR in a suspension microarray facilitates rapid diagnosis of lung cancer.
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PMID:Combined detection of p53, p16, Rb, and EGFR mutations in lung cancer by suspension microarray. 2008 63

The patient was a 58-year-old male with small cell lung cancer [T2N1M1 (HEP) ED case] who was treated systemic chemotherapy with 2 courses of CDDP+CPT-11 and 3 courses of CBDCA+PTX. After 5 courses of chemotherapy, the total response was stable disease (SD). Because the primary lesion had achieved a minor response, however, liver metastasis evidenced no change. Because of his good performance status, he was immediately treated by hepatic arterial infusion chemotherapy ( HAI) using CPT-11 to control the liver metastasis. After the HAI of weekly CPT-11 during eleven months until progression of primary lung lesion, no change in size of the liver metastasis was recognized with decreasing ProGRP (18,400 -->5,800). HAI is considered very useful for disease control without progression and for good quality of life.
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PMID:[A case of small cell lung cancer (extensive disease) with liver metastasis acquiring stable disease by hepatic arterial infusion chemotherapy]. 2033 90

The goal of this study was to characterize and classify pulmonary neuroendocrine tumors based on array comparative genomic hybridization (aCGH). Using aCGH, we performed karyotype analysis of 33 small cell lung cancer (SCLC) tumors, 13 SCLC cell lines, 19 bronchial carcinoids, and 9 gastrointestinal carcinoids. In contrast to the relatively conserved karyotypes of carcinoid tumors, the karyotypes of SCLC tumors and cell lines were highly aberrant. High copy number (CN) gains were detected in SCLC tumors and cell lines in cytogenetic bands encoding JAK2, FGFR1, and MYC family members. In some of those samples, the CN of these genes exceeded 100, suggesting that they could represent driver alterations and potential drug targets in subgroups of SCLC patients. In SCLC tumors, as well as bronchial carcinoids and carcinoids of gastrointestinal origin, recurrent CN alterations were observed in 203 genes, including the RB1 gene and 59 microRNAs of which 51 locate in the DLK1-DIO3 domain. These findings suggest the existence of partially shared CN alterations in these tumor types. In contrast, CN alterations of the TP53 gene and the MYC family members were predominantly observed in SCLC. Furthermore, we demonstrated that the aCGH profile of SCLC cell lines highly resembles that of clinical SCLC specimens. Finally, by analyzing potential drug targets, we provide a genomics-based rationale for targeting the AKT-mTOR and apoptosis pathways in SCLC.
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PMID:Array comparative genomic hybridization-based characterization of genetic alterations in pulmonary neuroendocrine tumors. 2061 70

Biological markers are urgently needed to improve the early detection, diagnosis and treatment of lung tumours. Over the past several years various promising biomarkers have emerged in the field of lung cancer. The poor prognosis associated with advanced lung cancer has resulted in attempts to develop lung cancer screening programs. The role of imaging and sputum cytology in lung cancer screening is the focus of much discussion, and efforts to find a suitable blood, sputum or exhaled breath biomarker for the detection of early lung cancer are ongoing. Regarding diagnosis, immunohistochemical profiling is a relatively well established adjunct to microscopic histology as a means of differentiating tumours originating in the lung from metastases from elsewhere. And, in particular in the case of non small cell lung cancer, a precise histological sub-classification of lung tumours is becoming clinically relevant in the choice of anti-tumour therapy, suggesting an increased and defined role for immunohistochemical markers. Molecular changes which correlate with the proposed subclassification of non-small cell lung cancer have also been identified. The treatment of lung cancer is dependant on the stage at the time of diagnosis. In particular, the decision whether or not to operate is dependant on the presence or absence of tumour cells in specific groups of mediastinal lymph nodes. The use of biomarkers can reveal microscopic lymph node metastases which would go unnoticed using conventional histology alone, and can provide early information about the presence of brain metastases. In addition, there is evidence that specific genetic factors predispose tumours to metastasis, which may have a role in the future risk-stratification of patients. Treatment with chemotherapy can be associated with significant toxicity, and is unfortunately not always successful in slowing the progression of lung cancer. The concept of individualized treatment depends on our ability to predict which tumours will respond to which medications. Numerous biomarkers have been suggested to have predictive value in response to chemotherapy, including ERCC-1 for response to cisplatin, beta-tubulin for response to taxanes, and RRM1 for response to gemcitabine. Increasing understanding of the EGFR pathway in NSCLC has led to the development of a class of medications aimed at inhibiting this pathway, including erlotinib, gefitinib and cetuximab. The efficacy of these medications seems to correlate with the presence of mutations in the EGFR gene. It has now been widely accepted that specific activating mutations in EGFR predicts the response of NSCLC to gefitinib and erlotinib. The failure of treatment with EGFR inhibitors also appears to correlate with both specific mutations in EGFR and with mutations in other proteins in the EGFR pathway. The importance of angiogenesis to tumour growth has led to interest in medications which inhibit angiogenesis. The vascular endothelial growth factor (VEGF) and its receptor are of particular interest. Once treatment has been initiated, biomarkers play an important role in patient monitoring. The serum levels of CYFRA-21-1 and CEA, as well serum nucleosome levels, correlate with the tumour's response to therapy. In addition, serum levels of circulating tumour cells, as well as the detection of specific mutations in circulating tumour DNA may be of clinical use in the future. This paper describes the current role of biomarkers in the detection, diagnosis and treatment of lung cancer, and presents data relating to the development of new biomarkers which are emerging as tools in the management of this difficult disease.
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PMID:Biological markers in lung cancer: A clinician's perspective. 2066 Sep 59

The anaplastic lymphoma kinase (ALK) inhibitor crizotinib will become an integral addition to the treatment of patients with non-small cell lung cancer (NSCLC) harboring genetic ALK translocations. The insulin-like growth factor receptor (IGF-1R) monoclonal antibody figitumumab, while initially promising, appears to increase toxicity and death in combination with chemotherapy in the treatment of patients with NSCLC of squamous histology; therefore, clinical development of this class of agents will need to proceed with caution. The histone deacetylation (HDAC) inhibitor vorinostat did not demonstrate an improvement in overall survival (OS) compared with placebo in a large randomized trial, but other agents in this class may have greater selectivity and efficacy. Inhibitors of the hedgehog (Hh) signaling pathways have some early clinical promise in both NSCLC and small cell lung cancer (SCLC), and larger studies using these agents are eagerly anticipated.
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PMID:Exciting new targets in lung cancer therapy: ALK, IGF-1R, HDAC, and Hh. 2067 9

The phamacogenetics is being used to predict whether the selected chemotherapy will be really effective and tolerable to the patient. Irinotecan, oxidized by CYP3A4 to produce inactive compounds, is used for treatment of various cancers including advanced non small cell lung cancer (NSCLC) patients. CYP3A4(*)16B polymorphism was associated with decreased metabolism of irrinotecan. Irinotecan is also metabolized by carboxylesterase to its principal active metabolite, SN-38, which is subsequently glucuronidated by UGT1As to form the inactive compound SN-38G. UGT1A1(*)28 and UGT1A1(*)6 polymorphisms were useful for predicting severe toxicity with NSCLC patients treated with irinotecan-based chemotherapy. Platinum-based compounds (cisplatin, carboplatin) are being used in combination with new cytotoxic drugs such as gemcitabine, paclitaxel, docetaxel, or vinorelbine in the treatment of advanced NSCLC. Cisplatin activity is mediated through the formation of cisplatin-DNA adducts. Gene polymorphisms of DNA repair factors are therefore obvious candidates for determinants of repair capacity and chemotherapy efficacy. ERCC1, XRCC1 and XRCC3 gene polymorphisms were a useful marker for predicting better survival in advanced NSCLC patients treated with platinum-based chemotherapy. XPA and XPD polymorphisms significantly increased response to platinum-based chemotherapy. These DNA repair gene polymorphisms were useful as a predictor of clinical outcome to the platinum-based chemotherapy. EGFR kinase inhibitors induce dramatic clinical responses in NSCLC patients with advanced disease. EGFR gene polymorphism in intron 1 contains a polymorphic single sequence dinucleotide repeat (CA-SSR) showed a statistically significant correlation with the gefitinib response and was appeared to be a useful predictive marker of the development of clinical outcome containing skin rashes with gefitinib treatment. The other polymorphisms of EGFR were also associated with increased EGFR promoter activity. EGFR gene mutations and polymorphisms were also associated with EGFR kinase inhibitors response and toxicity.
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PMID:Gene Polymorphisms and Chemotherapy in Non-small Cell Lung Cancer. 2071 67


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