Gastric cancer in the era of molecularly targeted agents: current drug development strategies

Arkenau, Hendrik‐Tobias

doi:10.1007/s00432-009-0583-7

Cited by 56 publications

(40 citation statements)

References 85 publications

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“…In particular, molecular therapies targeted against EGFR increase the impact of treatment in breast and colorectal cancer patients (26,27). Recently, it was shown that therapy targeted against EGFR had a beneficial effect on gastric cancer patients in clinical trials (28,29). IRAK1 and subsequent NF-kB activation is associated with poor prognosis and invasion in gastric cancer (30,31).…”

Section: Discussionmentioning

confidence: 99%

Clinical Significance of miR-146a in Gastric Cancer Cases

Kogo

Mimori

Tanaka

et al. 2011

Clinical Cancer Research

198

180

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Purpose: The profiles of microRNAs change significantly in gastric cancer. MiR-146a is reported to be a tumor suppressor in pancreatic cancer, breast cancer, and prostate cancer. We investigated the clinical significance of miR-146a in gastric cancer, in particular focusing on hypothetical miR-146a target genes, such as epidermal growth factor receptor (EGFR) and interleukin-1 receptor-associated kinase (IRAK1).Experimental Design: We examined miR-146a levels in 90 gastric cancer samples by q-real-time (qRT)-PCR and analyzed the association between miR-146a levels and clinicopathologic factors and prognosis. The regulation of EGFR and IRAK1 by miR-146a was examined with miR-146a-transfected gastric cancer cells. Moreover, we analyzed the association between miR-146a levels and the G/C single nucleotide polymorphism (SNP) within pre-miR-146a seed sequences in 76 gastric cancer samples, using direct sequencing of genomic DNA.Results: In 90 clinical samples of gastric cancer, miR-146a levels in cancer tissues were significantly lower than those in the corresponding noncancerous tissue (P < 0.001). Lower levels of miR-146a were associated with lymph node metastasis and venous invasion (P < 0.05). Moreover, a lower level of miR-146a was an independent prognostic factor for overall survival (P ¼ 0.003). Ectopic expression of miR-146a inhibited migration and invasion and downregulated EGFR and IRAK1 expression in gastric cancer cells. In addition, G/C SNP within the pre-miR-146a seed sequence significantly reduced miR-146a levels in the GG genotype compared with the CC genotype.Conclusions: MiR-146a contains an SNP, which is associated with mature miR-146a expression. MiR146a targeting of EGFR and IRAK1 is an independent prognostic factor in gastric cancer cases. Clin Cancer Res; 17(13); 4277-84. Ó2011 AACR.

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Section: Discussionmentioning

confidence: 99%

Clinical Significance of miR-146a in Gastric Cancer Cases

Kogo

Mimori

Tanaka

et al. 2011

Clinical Cancer Research

198

180

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“…Numerous studies have shown that receptor tyrosine kinases such as the vascular growth factor receptor (VEGFR; Mannell et al, 2012) epidermal growth factor receptor (EGFR) and insulin/insulin-like growth factor receptors (InR/ IGF-Rs) play prominent roles in signaling cell proliferation and differentiation (reviewed by Schlessinger, 2004). Misregulation of both pathways is often causative for tumor development and progression through their effects on uncontrolled cell growth, inhibition of apoptosis, angiogenesis, and tumor-associated inflammation (Witte et al, 2009;Alvarez et al, 2010;Antonarakis et al, 2010;Arkenau, 2009). Determining how growth and differentiation are coordinated by these pathways is thus essential to understanding normal development, as well as disease states such as cancer.…”

Section: Introductionmentioning

confidence: 99%

The drosophila Arf GEF steppke controls MAPK activation in EGFR signaling

Hahn

Fuss

Peters

et al. 2013

Journal of Cell Science

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SummaryGuanine nucleotide exchange factors (GEFs) of the cytohesin protein family are regulators of GDP/GTP exchange for members of the ADP ribosylation factor (Arf) of small GTPases. They have been identified as modulators of various receptor tyrosine kinase signaling pathways including the insulin, the vascular epidermal growth factor (VEGF) and the epidermal growth factor (EGF) pathways. These pathways control many cellular functions, including cell proliferation and differentiation, and their misregulation is often associated with cancerogenesis. In vivo studies on cytohesins using genetic loss of function alleles are lacking, however, since knockout mouse models are not available yet. We have recently identified mutants for the single cytohesin Steppke (Step) in Drosophila and we could demonstrate an essential role of Step in the insulin signaling cascade. In the present study, we provide in vivo evidence for a role of Step in EGFR signaling during wing and eye development. By analyzing step mutants, transgenic RNA interference (RNAi) and overexpression lines for tissue specific as well as clonal analysis, we found that Step acts downstream of the EGFR and is required for the activation of mitogen-activated protein kinase (MAPK) and the induction of EGFR target genes. We further demonstrate that step transcription is induced by EGFR signaling whereas it is negatively regulated by insulin signaling. Furthermore, genetic studies and biochemical analysis show that Step interacts with the Connector Enhancer of KSR (CNK). We propose that Step may be part of a larger signaling scaffold coordinating receptor tyrosine kinase-dependent MAPK activation.

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“…Epidemiological and pathological studies have shown that gastric cancer is a complex, multistep and multifactorial process, involving numerous genetic and epigenetic alterations, such as abnormalities in growth factors/receptors, angiogenic factors, cell cycle regulators and DNA mismatch repair (MMR) genes. These abnormalities also define biological characteristics of gastric cancer cells, which are capable of serving as therapeutic targets for gastric cancer (5).…”

Section: Introductionmentioning

confidence: 99%

Polymorphisms of mismatch repair gene hMLH1 and hMSH2 and risk of gastric cancer in a Chinese population

et al. 2011

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Abstract. The purpose of this study was to determine the genotype and allele frequencies of hMLH1 (-93G>A and I219V) and hMSH2 (-118T>C and IVS12-6T>C) polymorphisms in patients with gastric carcinoma and normal controls, and to evaluate the association between these polymorphisms and the risk of gastric cancer in a hospital-based Chinese population. Genomic DNA was extracted from peripheral blood lymphocytes. A TaqMan assay was used to determine the genotype and allele frequencies of hMLH1 and hMSH2 polymorphisms in data obtained from 554 gastric cancer cases and 592 controls. Unconditional logistic regression was used to assess the association between the four single nucleotide polymorphisms (SNPs) and gastric carcinoma risk. No evidence of an association among any of the four polymorphisms and the risk of gastric cancer was observed. However, when gastric cancer patients were further stratified by age, gender, smoking status, alcohol use and clinicopathological characteristics, and compared with the control populations, the combined variant genotype hMSH2 -118T>C (TC+CC) was not only associated with an increased risk of gastric cancer in subgroups of younger subjects [ages ≤63years; adjusted odds ratio (OR)=1.51, 95% confidence interval (CI), 1.05-2.16], but also with diffuse tumors (adjusted OR=1.41, 95% CI, 1.01-1.96). These data indicate that the polymorphisms of -93G>A, I219V and IVS12-6T>C are not associated with the risk of gastric cancer. However, hMSH2-118T>C combined with variant genotypes (TC+CC) may confer a potential risk of gastric cancer in the Chinese population.

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Gastric cancer in the era of molecularly targeted agents: current drug development strategies

Cited by 56 publications

References 85 publications

Clinical Significance of miR-146a in Gastric Cancer Cases

Clinical Significance of miR-146a in Gastric Cancer Cases

The drosophila Arf GEF steppke controls MAPK activation in EGFR signaling

Polymorphisms of mismatch repair gene hMLH1 and hMSH2 and risk of gastric cancer in a Chinese population

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