Biomarker analysis in a phase III study of pemetrexed–carboplatin versus etoposide–carboplatin in chemonaive patients with extensive-stage small-cell lung cancer

Smit, Egbert F.; Ma, Shenglin; Mullaney, Bp; Myrand, Sp; Scagliotti, Giorgio Vittorio; Lorigan, Paul; Reck, Martin; Ciuleanu, Tudor-Eliade; Pawel, Joachim von; Karaseva, N.; Szczęsna, Aleksandra; Ohannesian, David W.; Powell, Emily; Hozak, R. R.; Hong, Shengyan; Guba, Sc; Thatcher, Nicholas

doi:10.1093/annonc/mdr563

Cited by 26 publications

(20 citation statements)

References 29 publications

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“…High GGH expression was shown to be associated with a higher risk of developing advanced toxicity to pemetrexed, a multi-targeted antifolate, in patients with advanced breast cancer (Llombart-Cussac et al 2007). Furthermore, several recently identified and characterized functionally significant genetic and epigenetic polymorphisms of GGH have been reported to predict response to and toxicity of antifolate-based treatment in patients with several cancers (Cheng et al 2004;Kim et al 2008;Koomdee et al 2012;Silva et al 2013;Smit et al 2012;Wang et al 2014) and inflammatory arthritis (Dervieux et al 2004;Hayashi et al 2009;Jekic et al 2013;Owen et al 2012;van der Straaten et al 2007;Yanagimachi et al 2011). Our data herein provide evidence that GGH modulation significantly influences expression and CpG DNA methylation of genes involved in important biological pathways that might account for the observed effects of GGH modulation on cancer risk, prognosis, and treatment response.…”

Section: Discussionsupporting

confidence: 54%

γ-Glutamyl hydrolase modulation significantly influences global and gene-specific DNA methylation and gene expression in human colon and breast cancer cells

et al. 2014

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c-Glutamyl hydrolase (GGH) plays an important role in folate homeostasis by catalyzing hydrolysis of polyglutamylated folate into monoglutamates. Polyglutamylated folates are better substrates for several enzymes involved in the generation of S-adenosylmethionine, the primary methyl group donor, and hence, GGH modulation may affect DNA methylation. DNA methylation is an important epigenetic determinant in gene expression, in the maintenance of DNA integrity and stability, and in chromatin modifications, and aberrant or dysregulation of DNA methylation has been mechanistically linked to the development of human diseases including cancer. Using a recently developed in vitro model of GGH modulation in HCT116 colon and MDA-MB-435 breast cancer cells, we investigated whether GGH modulation would affect global and gene-specific DNA methylation and whether these alterations were associated with significant gene expression changes. In both cell lines, GGH overexpression decreased global DNA methylation and DNA methyltransferase (DNMT) activity, while GGH inhibition increased global DNA methylation and DNMT activity. Epigenomic and gene expression analyses revealed that GGH modulation influenced CpG promoter DNA methylation and gene expression involved in important biological pathways including cell cycle, cellular development, and cellular growth and proliferation. Some of the observed altered gene expression appeared to be regulated by changes in CpG promoter DNA methylation. Our data suggest that the GGH modulation-induced changes in total intracellular folate concentrations and content of long-chain Electronic supplementary material The online version of this article

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Section: Discussionsupporting

confidence: 54%

γ-Glutamyl hydrolase modulation significantly influences global and gene-specific DNA methylation and gene expression in human colon and breast cancer cells

et al. 2014

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“…This study investigated SNPs at the XRCC3, XPD, ERCC1, GARFT, DHFR, and TS genes, but none of these SNPs was found to be a useful predictor of treatment efficacy. However, SNPs in regions including/interacting with the RFC and GGH genes were associated with differences in OS in another recent study in small-cell lung cancer patients from a randomized phase III trial comparing pemetrexed-carboplatin with etoposide-carboplatin [26]. Conversely the MTHFR-A1298A genotype was associated with significantly shorter OS in patients with recurrent or metastatic head and neck cancer treated within a phase II trial of pemetrexed and bevacizumab [27].…”

Section: Discussionmentioning

confidence: 98%

Pharmacogenetic study of patients with advanced non-small cell lung cancer (NSCLC) treated with second-line pemetrexed or pemetrexed–carboplatin

et al. 2012

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“…This among other polymorphisms has been suggested as molecular predictive markers by some publications in both SCLC and NSCLC [32,33]; but the results are not encouraging enough to promote these tests in the regular practice.…”

Section: Pemetrexedmentioning

confidence: 96%

Pharmacogenomics in the Treatment of Lung Cancer: an Update

et al. 2015

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Significant advances have been made in the analysis of the human genome in the first decades of the 21st century and understanding of tumor biology has matured greatly. The identification of tumor-associated mutations and the pathways involved has led to the development of targeted anticancer therapies. However, the challenge now in using chemotherapy to treat nonsmall-cell lung cancer is to identify more molecular markers predictive of drug sensitivity and determine the optimal drug sequences in order to tailor treatment to each patient. This approach could permit selection of patients who could benefit most from a specific type of chemotherapy by matching their tumor and individual genetic profile. Nevertheless, this potential has been limited so far by reliance on the single biomarker approach, though this is now on the way to being overcome through whole genome studies.

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Biomarker analysis in a phase III study of pemetrexed–carboplatin versus etoposide–carboplatin in chemonaive patients with extensive-stage small-cell lung cancer

Cited by 26 publications

References 29 publications

γ-Glutamyl hydrolase modulation significantly influences global and gene-specific DNA methylation and gene expression in human colon and breast cancer cells

γ-Glutamyl hydrolase modulation significantly influences global and gene-specific DNA methylation and gene expression in human colon and breast cancer cells

Pharmacogenetic study of patients with advanced non-small cell lung cancer (NSCLC) treated with second-line pemetrexed or pemetrexed–carboplatin

Pharmacogenomics in the Treatment of Lung Cancer: an Update

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