Individualized treatment of gastric cancer: Impact of molecular biology and pathohistological features

Dittmar, Y.; Settmacher, Utz

doi:10.4251/wjgo.v7.i11.292

Cited by 15 publications

(11 citation statements)

References 78 publications

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“…Targeted therapies aimed at specific cancer biomarkers have led to recent improvements in drug response and preventing drug resistance. However, disappointing results were achieved in most phase III clinical trials [ 28 , 4 , 3 ], and to date, only two drugs have been licensed. Trastuzumab was the first targeted agent approved as a first line therapy for HER2 positive patients, whereas ramucirumab was approved as a second-line treatment for patients with metastatic gastric cancer [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

PFK15, a Small Molecule Inhibitor of PFKFB3, Induces Cell Cycle Arrest, Apoptosis and Inhibits Invasion in Gastric Cancer

et al. 2016

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PFKFB3 (6-phosphofructo-2-kinase) synthesizes fructose 2,6-bisphosphate (F2,6P2), which is an allosteric activator of 6-phosphofructo-1-kinase (PFK-1), the rate-limiting enzyme of glycolysis. Overexpression of the PFKFB3 enzyme leads to high glycolytic metabolism, which is required for cancer cells to survive in the harsh tumor microenvironment. The objective of this study was to investigate the antitumor activity of PFK15 (1-(4-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one), a small molecule inhibitor of PFKFB3, against gastric cancer and to explore its potential mechanisms. The effects of PFK15 on proliferation, apoptosis and cell cycle progression in gastric cancer cells were evaluated by cytotoxicity and apoptosis assays, flow cytometry, and western blotting. In addition, the invasion inhibition effects of PFK15 were measured by transwell invasion assay and western blot analysis, and a xenograft tumor model was used to verify the therapeutic effect of PFK15 in vivo. Results showed that PFK15 inhibited the proliferation, caused cell cycle arrest in G0/G1 phase by blocking the Cyclin-CDKs/Rb/E2F signaling pathway, and induced apoptosis through mitochondria in gastric cancer cells. Tumor volume and weight were also significantly reduced upon intraperitoneal injection with PFK15 at 25 mg/kg. In addition, PFK15 inhibited the invasion of gastric cancer cells by downregulating focal adhesion kinase (FAK) expression and upregulating E-cadherin expression. Taken together, our findings indicate that PFK15 is a promising anticancer drug for treating gastric cancer.

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Section: Discussionmentioning

confidence: 99%

PFK15, a Small Molecule Inhibitor of PFKFB3, Induces Cell Cycle Arrest, Apoptosis and Inhibits Invasion in Gastric Cancer

et al. 2016

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“…The majority of patients are diagnosed at an advanced stage, with 50%–75% presenting with regional lymph node metastasis, and the overall five-year survival rate of advanced stage GC patients is approximately 15%2. Although multimodality therapy has advanced, the prognosis and overall survival rate of patients with gastric cancer are still low3. Thus, to improve the prognosis of such patients, novel strategies need to be developed and established.…”

mentioning

confidence: 99%

The clinicopathological and prognostic significance of PD-L1 expression in gastric cancer: a meta-analysis of 10 studies with 1,901 patients

Zhang

Dong

Liu

et al. 2016

Sci Rep

123

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The prognostic value of programmed death-ligand 1 (PD-L1) in gastric cancer (GC) remains controversial. To clarify this problem, we performed a meta-analysis of research studies identified in the PubMed, EMBASE and the Cochrane Library databases. A total of 1,901 patients in 10 studies were enrolled in this meta-analysis, and the pooled hazard ratio (HR) of 1.64 (95% CI 1.11 to 2.43; P = 0.01) indicated that PD-L1 expression is associated with a shorter overall survival (OS). The pooled odds ratios (ORs) indicated that PD-L1 expression was associated with tumour size (OR = 1.87, 95% CI 1.25 to 2.78; P = 0.002) and lymph node status (OR = 2.17, 95% CI 1.04 to 4.52; P = 0.04). However, PD-L1 had no correlation with gender, age, cancer location, differentiation, depth of invasion, and tumour stage. This meta-analysis indicates that PD-L1 expression is a valuable predictor of the prognosis of patients with GC. PD-L1 expression could be used for identifying a subgroup of patients, who would potentially benefit from targeted therapy against PD-1 or PD-L1. Well-designed large-cohort studies are needed to confirm these findings.

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“…Improved understanding of the molecular biology of GC and the development of targeted molecular therapy is likely to improve the prognosis of GC patients [ 43 , 44 ]. Trastuzumab, a monoclonal antibody targeting HER2, is used in the treatment of patients with HER2 positive, inoperable, locally advanced, recurrent, or metastatic GC, although individualized treatment for GC according to HER2 status has not been done.…”

Section: Discussionmentioning

confidence: 99%

Prognostic implications of HER2 heterogeneity in gastric cancer

Motoshima

Yonemoto

Kamei³

et al. 2018

Oncotarget

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The prognostic implications of human epidermal growth receptor 2 (HER2) heterogeneity in gastric cancer (GC) are not well established. Therefore, the aim of the present study was to determine to the effect of HER2 status on the prognosis of GC patients. We retrieved data on 248 pathologically-confirmed, consecutive patients with primary adenocarcinoma of the stomach or gastro-esophageal junction who underwent surgical resection at Kurume University Medical Center between July 2000 and December 2012. HER2 status was classified as HER2 positive or negative and HER2 heterogeneity or homogeneity. The endpoint was overall survival (OS), which was compared using the generalized Wilcoxon test. HER2 status was positive in 36 patients (14.5%) and negative in 212 patients (85.5%). Among the 36 HER2 positive patients, 25 patients (69.4%) had HER2 heterogeneity and the remaining 11 patients (30.6%) had HER2 homogeneity. Among the 141 patients with stage III or IV disease, the prognosis of the HER2 homogeneity group was significantly worse than that of the HER2 heterogeneity group (p = 0.019; median OS 193 and 831 days, respectively). The prognosis was not significantly different between the HER2 positive group and the HER2 negative group (p = 0.84; median OS 552 and 556 days, respectively). The present study was conducted with small samples, however, the results of the study suggest that HER2 homogeneity but not HER2 positivity may represent a prognostic indicator in GC.

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Individualized treatment of gastric cancer: Impact of molecular biology and pathohistological features

Cited by 15 publications

References 78 publications

PFK15, a Small Molecule Inhibitor of PFKFB3, Induces Cell Cycle Arrest, Apoptosis and Inhibits Invasion in Gastric Cancer

PFK15, a Small Molecule Inhibitor of PFKFB3, Induces Cell Cycle Arrest, Apoptosis and Inhibits Invasion in Gastric Cancer

The clinicopathological and prognostic significance of PD-L1 expression in gastric cancer: a meta-analysis of 10 studies with 1,901 patients

Prognostic implications of HER2 heterogeneity in gastric cancer

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