Rafael Rosell

..The knockdown of PARP1 and EZH2 abrogated SCLC growth. These findings provide the basis for novel predictive markers and new treatment strategies in SCLC, for which there is now a paucity of available therapies...

..We aimed to assess the safety and efficacy of erlotinib compared with standard chemotherapy for first-line treatment of European patients with advanced EGFR-mutation positive NSCLC...

..In addition, NFKBIA and DUSP22 gene status was also determined...

..It is plausible that several genetically defined subclasses of EGFR mutations could help to improve current clinical outcomes by combining erlotinib or gefitinib with other targeted drugs...

..A 15-gene signature has identified JBR.10 patients who are more sensitive to adjuvant chemotherapy...

..However, the presence of EGFR mutations can only imperfectly predict outcome. We hypothesized that progression-free survival could be influenced both by the pretreatment EGFR T790M mutation and by components of DNA repair pathways...

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..Mechanisms of resistance to reversible EGFR TKIs should be further clarified and could be related to modifications in DNA repair...

..Hypoxia-inducible factor-1a expression levels analyzed by real-time quantitative PCR in surgery specimens after platinum/gemcitabine therapy do not correlate with the outcome of patients with stage II/III NSCLC...

..Genes involved in spindle formation, centrosome functions and mRNA transport along the microtubule tracks should provide further information on potential markers of docetaxel resistance...

..1-month progression-free survival, and 19-month median survival. CHRNA3 (rs1051730) genotyping can improve customized chemotherapy based on tumor assessment of ERCC1 mRNA in stage IV NSCLC with PS 0...

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..Ribonucleotide reductase subunit M1 (RRM1) is involved in DNA synthesis and repair and in gemcitabine metabolism, and the excision repair cross-complementing group 1 (ERCC1) gene has been related to cisplatin activity...

..ERCC1 is one of several proteins involved in the repairosome, where other DNA repair genes, such as BRCA1, are also central to cisplatin resistance...

..One can thus envision that substantial improvements in therapeutic outcome could benefit from the integration of tailored ribonucleotide reductase-dependent chemotherapy, ribonucleotide reductase antisense therapy, and targeted therapy...

..However, the number of tumor cells in a sample is often insufficient for EGFR assessment...

..Patients are randomized to the control arm of cisplatin/docetaxel or to the experimental arm, where docetaxel is combined with cisplatin or gemcitabine according to ERCC1 levels. To date, 86 patients have been included...

..Preliminary findings that a subset of gemcitabine/cisplatin-treated patients with low ERCC1 and RRM1 mRNA levels show a significantly longer survival and highlight the possibilities of individually tailored chemotherapy...

..In an exploratory analysis, we also examined the effect of RAP80 and Abraxas mRNA levels...

..Methylation-dependent transcriptional silencing of 14-3-3sigma, a major G2-M checkpoint control gene, could be a predictor of longer survival...

..The predictive value of beta-tubulin III, stathmin and RRM1 should be tested in prospective customized chemotherapy trials, the results of which will help tailor chemotherapy to improve patient survival...

..Second-line EGFR TKIs improved survival in patients receiving first-line cisplatin-based treatment. Unmethylated CHFR predicts increased survival to EGFR TKIs...

..This review highlights the numerous molecular biology findings in the field of lung cancer with potential therapeutic impact in both the near and distant future...

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..The presence of EGFR mutations is a major determinant of gefitinib response, and EGFR tyrosine kinase inhibitors should be tested in clinical trials of first-line treatment of lung adenocarcinomas harboring EGFR mutations...

..Carriers of the MTHFR 677T allele could benefit from supplementation with folic acid and vitamin B12. The Spanish Lung Cancer Group has undertaken a phase III randomized trial to elucidate this concept...

..Non-small-cell lung cancer (NSCLC) is a disseminated disease in 50% of cases, with a gloomy prognosis and median survivals of < 1 year...

..We evaluated the feasibility of large-scale screening for EGFR mutations in such patients and analyzed the association between the mutations and the outcome of erlotinib treatment...

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..Immunohistochemistry (IHC) with mutation-specific antibodies may be an ancillary method of detecting EGFR mutations in lung cancer patients...

..These findings are presented in this article, as well as their relevance in customising chemotherapy - illustrated by a hypothetical model guiding treatment decisions in the management of NSCLC...

..The five articles in this edition of CCR Focus will address the various mechanisms of EGFR pathway activation and provide insight into the potential for translation into clinical relevance...

..020) compared with those in the top quartile. BRCA1 expression is potentially an important tool for use in cancer management and should be assessed for predicting differential chemosensitivity and tailoring chemotherapy in lung cancer...

..To address whether preoperative chemotherapy plus surgery or surgery plus adjuvant chemotherapy prolongs disease-free survival compared with surgery alone among patients with resectable non-small-cell lung cancer...

..Future clinical trials in NSCLC will include tailored and multitargeted therapy and pemetrexed represents a significant step forward in this direction...

..The sensitivity to EGFR TKIs could be greatly influenced by the expression of genes involved in the repair of DNA double-strand breaks by homologous recombination and non-homologous end joining...

..Methylation of the promoter of the MGMT gene and MGMT protein expression are recognized as predictive markers for response to alkylating chemotherapy in glioblastoma (GB)...

..These findings highlight the importance of continual learning, and decision-making strategies for customizing treatment should reflect the limitations of our knowledge...

..Translational clinical trials are warranted in order to detect the subgroups of patients resistant to radiotherapy who may derive benefit from novel therapies, including antiangiogenic drugs...

..Furthermore, sporadic ovarian cancer patients with low levels of BRCA1 mRNA have longer survival following platinum-based chemotherapy than patients with high levels of BRCA1 mRNA...

..We review here the clinical benefits of targeted therapy with erlotinib and gefitinib in white and Asian nonsmall-cell lung cancer patients...

..K-ras mutations in serum correlated significantly with survival (P=0.01)...

..In this article, the authors try to highlight the more relevant aspects regarding these issues, primarily focused on the potential role of ERCC1, RRM1, XPD and BRCA1 expression profiling as predictors of anticancer drug efficacy...

..MGMT methylation can be assessed in serum DNA. By assessing ERCC1 mRNA, cisplatin adducts, XPD polymorphism, Ape 1, and MGMT, we can obtain a complete genetic profile, which can be used in real translational research...

..This report provides a review on the breast cancer susceptibility gene 1, a promising gene determinant of response to different types of chemotherapy and its potential applications as a new molecular marker in lung cancer...

..At the preclinical level, small interfering RNA sequences have been used successfully to neutralize multiple abnormal components of the Wnt pathway...

..Some DNA repair genes, like ERCC1, have been shown to be crucial in predicting cisplatin resistance and can be used for tailoring cisplatin-based chemotherapy...

..Although GBM grows within the skull, we investigated the concordance of methylation in glioma tissue, and paired serum DNA and the potential correlation with response and time to progression...

..At present, molecular markers, such as ERCC1, represent a potential parameter to help guide clinical treatment decisions. Prospective pharmacogenomic studies are therefore a research priority in NSCLC...

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..However, patients ultimately relapse, indicating that other genetic factors could influence outcome in such patients. We hypothesized that PFS could be influenced by the expression of genes in DNA repair pathways...

..With the gene corral that will emerge from this trial, we will create an up-front diagnostic test for selecting the most appropriate gemcitabine plus cisplatin regimen for the treatment of non-small cell lung cancer...

..Herein, we discuss current knowledge regarding gene expression and polymorphisms of DNA repair enzymes in regard to cancer susceptibility and response to chemotherapy...

..It also appears from xenograft data that C225 enhances the sensitivity of tumors to radiation and docetaxel or the combination...

..Intense research activity is ongoing to validate known predictive markers and to discover new tools which maximize clinical benefit using erlotinib. However, there is no conclusive evidence, as yet, linking response to survival...

..The review focuses on a number of new targeted agents/chemotherapy drugs now in clinical trials directed at improving NSCLC management. Mature results regarding their activity and usefulness can be expected in the near future...

..To clarify this important issue, the Spanish Lung Cancer Group has opened a Phase III trial comparing erlotinib with chemotherapy in stage IV NSCLC patients with EGFR mutations. This study is open to other European institutions...

..The Vancouver programme included > 140 invited speakers throughout the 'meet the professor', plenary and interactive sessions, as well as 300 oral and 500 poster presentations...

..Large-scale screening for EGFR mutations in such patients is feasible for predicting response to TKIs and thus guiding treatment...

..Non-hematologic toxicities were mild in all three schedules. For future studies, schedule A with lower doses is recommended...

..Hopefully, the assessment of Src and of STAT-3 can be implemented as predictive markers...

..Mechanisms of resistance to pemetrexed need to be investigated, including the potential role of TS messenger RNA. In summary, pemetrexed has emerged as a promising new cytotoxic drug in the arsenal of chemotherapy treatments for NSCLC...

..The results indicate that our method is highly sensitive, reliable and reproducible, and thus, it suitable for population-based studies to quantify in vitro DNA-repair deficiencies...

..PM02734 is a closely related derivative of KF with similar activity and characteristics. Herein, we summarize the studies of PM02734 and future clinical perspectives...

..In addition, Wnt signaling pathways also play a crucial role in normal tissue regeneration and stem cell self-renewal, raising the possibility of controlling immature tumor stem cells...