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Query: UMLS:C0024623 (gastric cancer)
 36,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite the progress in cancer therapeutics and chemotherapy development with the introduction of new drugs, advanced gastric cancer continues to have an extremely poor prognosis and with limited treatment options. The introduction of new antitarget drugs has introduced a new perspective in cancer treatment in general and gastric cancer in particular. Nevertheless, few studies have been developed with this generation of drugs. The monoclonal antibody antiepidermal growth factor receptor (EGFR) cetuximab and the antiangiogenic bevacizumab have been used in phase I and II studies with good results, which need to be confirmed in new phase III studies. The carcinogenesis of this tumor provides information regarding two transcription and signaling pathways of great interest and with therapeutic potential. Infection by Helicobacter pylori is recognized as the cause of gastric cancer development, and there are two elements that play an important role in this process: the CagA gene, whose protein is introduced in the cell by H. pylori initiates the process; and the hedgehog signaling pathway, which regulates the gastric mucosa and is very frequently activated in gastric cancer. Taking action on these agents may be a new and effective method of treating gastric cancer, and therefore must be researched.
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PMID:New drugs in the treatment of gastric tumors. 1849 Feb 41

Overexpression of the transcription factor Sp1 may play a critical role in human gastric cancer angiogenesis. In the present studies, we determined whether targeting Sp1 has a therapeutic benefit. Treatment with mithramycin A (MIT) suppressed the expression of Sp1 and its downstream target genes in both human gastric cancer cell culture and tumors growing in nude mice. The molecular responses were accompanied by a significant inhibition of gastric cancer angiogenesis, growth and metastasis. Conversely, treatment with bevacizumab (BVZ), a neutralizing antibody against VEGF A, suppressed human gastric cancer growth in nude mice in a dose-dependent manner. Gene expression analyses revealed that treatment with low dose of BVZ substantially upregulated the expression of Sp1 and its downstream target genes, including VEGF and EGFR, in tumor tissues, whereas it did not have this effect on gastric cancer cells in culture. Combined treatment with BVZ and MIT produced synergistic tumor suppression, which was consistent with suppression of the expression of Sp1 and its downstream target genes. Thus, treatment with BVZ may block VEGF function but activate the pathway of its expression via positive feedback. Collectively, Sp1 is an important regulator of the expression of multiple angiogenic factors and functional status of Sp1 signaling pathway may profoundly affect the angiogenic phenotype of and effectiveness of antiangiogenic strategies for human gastric cancer.
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PMID:Targeted inhibition of Sp1-mediated transcription for antiangiogenic therapy of metastatic human gastric cancer in orthotopic nude mouse models. 1857 62

HER2 overexpression is observed in 5-25% of gastric cancers. Lapatinib is a dual inhibitor of the epidermal growth factor receptor and HER2 tyrosine kinase. We examined the antitumor effect of lapatinib in gastric cancer cell lines. Lapatinib induced selective and potent growth inhibition in two HER2-amplified gastric cancer cell lines (SNU-216 and NCI-N87). Lapatinib inhibited the phosphorylation of HER2, EGFR and downstream signaling proteins, resulting in G1 arrest in both cell lines with down-regulation of cMyc and induction of p27kip1. Lapatinib also induced apoptosis in NCI-N87 which has high HER2 amplification ratio. Lapatinib combined with 5-fluorouracil, cisplatin, oxaliplatin or paclitaxel showed an additive or synergistic effect. These results provide a rationale for the future clinical trials of lapatinib combined with cytotoxic drugs in the treatment of HER2-positive gastric cancer.
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PMID:The growth inhibitory effect of lapatinib, a dual inhibitor of EGFR and HER2 tyrosine kinase, in gastric cancer cell lines. 1877 37

Genomic copy number aberrations (CNAs) are believed to play a major role in the development and progression of human cancers. Although many CNAs have been reported in gastric cancer, their genome-wide transcriptional consequences are poorly understood. In this study, to reveal the impact of CNAs on genome-wide expression in gastric cancer, we analysed 30 cases of gastric cancers for their CNAs by array comparative genomic hybridization (array CGH) and 24 of these 30 cases for their expression profiles by oligonucleotide-expression microarray. We found that with the application of laser microdissection, most CNAs were detected at higher frequency than in previous studies. Notably, gain at 20q13 was detected in almost all cases (97%), suggesting that this may play an important role in the pathogenesis of gastric cancer. By comparing the array CGH data with expression profiles of the same samples, we showed that both genomic amplification and deletion strongly influence the expression of genes in altered genomic regions. Furthermore, we identified 125 candidate genes, consisting of 114 up-regulated genes located in recurrent regions (>10%) of amplification and 11 down-regulated genes located in recurrent regions of deletion. Up-regulation of several candidate genes, such as CDC6, SEC61G, ANP32E, BYSL and FDFT1, was confirmed by immunohistochemistry. Interestingly, some candidate genes were localized at genomic loci adjacent to well-known genes such as EGFR, ERBB2 and SMAD4, and concordantly deregulated by genomic alterations. Based on these results, we propose that our list of candidate genes may contain novel genes involved in the pathogenesis of advanced gastric cancer.
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PMID:Genome-wide analysis of DNA copy number alterations and gene expression in gastric cancer. 1879 23

The overall survival of gastric cancer patients remains poor despite efforts and advances in its prevention, diagnosis, and treatment. The development of new therapies is crucial for the effective control of this disease. An increasing number of genetic and epigenetic alterations have been associated with distinct histological types of gastric cancer. In this review, we will discuss the involvement of E-cadherin, EGFR, ERBB2, MMR genes, KRAS, and PIK3CA in the development and progression of gastric cancer and their role as biomarkers or as novel putative targets for therapy.
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PMID:Molecular targets and biological modifiers in gastric cancer. 1901 93

This prospective study was conducted with the Korean Cancer Study Group to evaluate the efficacy and safety of cetuximab combined with modified FOLFOX6 (mFOLFOX6) as first-line treatment in recurrent or metastatic gastric cancer and to identify potential predictive biomarkers. Patients received cetuximab 400 mg m(-2) at week 1 and 250 mg m(-2) weekly thereafter until disease progression. Oxaliplatin (100 mg m(-2)) and leucovorin (100 mg m(-2)) were administered as a 2-h infusion followed by a 46-h continuous infusion of 5-fluorouracil (2400 mg m(-2)) every 2 weeks for a maximum of 12 cycles. Biomarkers potentially associated with efficacy were analysed. Among 38 evaluable patients, confirmed response rate (RR) was 50.0% (95% CI 34.1-65.9). Median time-to-progression (TTP) was 5.5 months (95% CI 4.5-6.5) and overall survival (OS) 9.9 months. Eleven patients having tumour EGFR expression by immunohistochemistry with low serum EGF and TGF-alpha levels showed a 100% RR compared to 37.0% in the remaining 27 patients (P<0.001). Moreover, ligand level increased when disease progressed in seven out of eight patients with EGFR expression and low baseline ligand level. No patient exhibited EGFR amplification or K-ras mutations. Gastric cancer patients with EGFR expression and low ligand levels had better outcomes with cetuximab/mFOLFOX6 treatment.
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PMID:Phase II study and biomarker analysis of cetuximab combined with modified FOLFOX6 in advanced gastric cancer. 1912 59

E-cadherin has a determinant role in tumour progression, acting as an invasion and metastasis suppressor. Germline mutations of E-cadherin gene (CDH1) occur in 30% of families with Hereditary Diffuse Gastric Cancer (HDGC); of these 23% are missense mutations. The CDH1 missense mutations described to date span the entire gene and some lead to significant functional consequences. In this study, we explored the hypothesis that mutations affecting different E-cadherin protein domains have distinct effects on cell motility. To accomplish our objective we characterized the effect of eleven HDGC CDH1 germline missense mutations (T118R, L214P, G239R, A298T, T340A, P373L, R749W, E757K, E781D, P799R and V832M) on cell motility. Further, we studied their effect on the activation of signalling pathways known to be relevant for cell motility such as the EGFR, Src kinase and MAPKs. CDH1 mutations localized on the extracellular and juxtamembrane domains, both affecting the integrity of the extracellular domain, led to increased cell motility accompanied by increased EGFR activation. Moreover, we observed that cells expressing extracellular mutants exhibit increased activation of Src kinase and p38 MAPK. Our results allowed the identification of the E-cadherin domains pivotal for cell motility, further demonstrated a genotype-phenotype correlation, and defined a subset of HDGC cases which may benefit from EGFR inhibitors.
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PMID:E-cadherin mutations and cell motility: a genotype-phenotype correlation. 1926 61

Cancers in the gastrointestinal system account for a large proportion of malignancies and cancer-related deaths with gastric cancer and colorectal cancer being the most common ones. For those patients in whom surgical resection is not possible, other therapeutic approaches are necessary. Disordered apoptosis has been linked to cancer development and treatment resistance. Apoptosis occurs via extrinsic or intrinsic signaling each triggered and regulated by many different molecular pathways. In recent years, the selective induction of apoptosis in tumor cells has been increasingly recognized as a promising approach for cancer therapy. A detailed understanding of the molecular pathways involved in the regulation of apoptosis is essential for developing novel effective therapeutic approaches. Apoptosis can be induced by many different approaches including activating cell surface death receptors (for example, Fas, TRAIL and TNF receptors), inhibiting cell survival signaling (such as EGFR, MAPK and PI3K), altering apoptosis threshold by modulating pro-apoptotic and anti-apoptotic members of the Bcl-2 family, down-regulating anti-apoptosis proteins (such as XIAP, survivin and c-IAP2), and using other pro-apoptotic agents. In this review, the authors reviewed the currently reported apoptosis-targeting approaches in gastrointestinal cancers.
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PMID:Targeting apoptosis as an approach for gastrointestinal cancer therapy. 1927 96

The present study investigated the potential difference between EGFR-mutated lung adenocarcinoma (ADC) and KRAS-mutated ADC in relation to past illness and family history. Among the 153 tumors examined, 33 (21.6%) were EGFR-mutated, and 22 (14.4%) were KRAS-mutated. The EGFR-mutated cases showed a significantly higher prevalence of past illness involving the gastric cancer in males (EGFR 3/8 (37.5%), KRAS 0/13 (0.0%), no mutation (NONE) 1/57 (1.8%); Fisher's exact test, P=0.0064) or uterine myoma in females (EGFR 8/25 (32.0%), KRAS 0/9 (0.0%), NONE 3/41 (7.3%); Fisher's exact test, P=0.0139). No association between the mutations and family history was found. The EGFR-mutated ADC is therefore likely to develop through a distinct carcinogenetic pathway from the others, but genetic backgrounds seemed unlikely to be determinant predisposing to the EGFR-mutated ADC.
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PMID:Significant association between EGFR-mutated lung adenocarcinoma and past illness from gastric cancer or uterine myoma: its implication in carcinogenesis. 1936 47

EGFR tyrosine kinase inhibitors have shown promising efficacy in the treatment of tumors with EGFR mutations and amplifications. However, tyrosine kinase inhibitors have also proven ineffective against most tumors with EGFR wild-type (WT) alleles. Although some genetic changes, including the KRAS mutation, have been shown to confer resistance to tyrosine kinase inhibitors, novel strategies for the treatment of cancer patients with tumors harboring EGFR WT alleles have yet to be thoroughly delineated. The principal objective of this study was to improve our current understanding of drug interactions between EGFR and MAP/ERK kinase (MEK) inhibitors in an effort to gain insight into a novel therapeutic strategy against EGFR WT tumors. Using a panel of human EGFR WT gastric cancer cell lines, we showed that gastric cancer cells harboring the KRAS mutation were selectively sensitive to MEK inhibition as compared with those cells harboring KRAS and PI3K mutations and KRAS WT alleles. However, all cell lines were found to be resistant to EGFR inhibition. The results from Western blots and phosphoprotein arrays showed that, in MEK inhibitor resistant cell lines, AKT was activated through the EGFR/HER3/PI3K pathway following AZD6244 (ARRY-142886) treatment. Blockade of this feedback mechanism through the targeting of MEK and EGFR resulted in detectable synergistic effects in some cell lines in vitro and in vivo. Our results provide the basis for a rational combination strategy against human EGFR WT gastric cancers, predicated on the understanding of cross-talk between the MEK and EGFR pathways.
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PMID:Combination of EGFR and MEK1/2 inhibitor shows synergistic effects by suppressing EGFR/HER3-dependent AKT activation in human gastric cancer cells. 1975 9


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