Stratification and delineation of gastric cancer signaling by in vitro transcription factor activity profiling and integrative genomics

Periasamy, Jayaprakash; Muthuswami, Muthulakshmi; Rao, Divya Bhaskar; Tan, Patrick; Ganesan, Kumaresan

doi:10.1016/j.cellsig.2014.01.017

Cited by 11 publications

(7 citation statements)

References 88 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Other approaches using in vitro transcription factor activity profiling and integrative genomics resulted in the identification of three categories of factors/pathways involved: highly activated signalling pathways resulting from mutations; constitutively activated stress responsive pathways; and consistently downregulated nuclear receptor responsive factors. This functional profiling illustrates the complexity of gastric cancer biology and might help in discriminating therapeutic targets and signalling interactions for future studies ( Periasamy et al , 2014 ). Thus, despite the rapidly evolving knowledge on gastric cancer cell biology, the same progress has not been made in the investigation of aberrant signalling in the vasculature.…”

Section: Discussionmentioning

confidence: 97%

Biomarker analyses in REGARD gastric/GEJ carcinoma patients treated with VEGFR2-targeted antibody ramucirumab

et al. 2016

View full text Add to dashboard Cite

Background:Angiogenesis inhibition is an important strategy for cancer treatment. Ramucirumab, a human IgG1 monoclonal antibody that targets VEGF receptor 2 (VEGFR2), inhibits VEGF-A, -C, -D binding and endothelial cell proliferation. To attempt to identify prognostic and predictive biomarkers, retrospective analyses were used to assess tumour (HER2, VEGFR2) and serum (VEGF-C and -D, and soluble (s) VEGFR1 and 3) biomarkers in phase 3 REGARD patients with metastatic gastric/gastroesophageal junction carcinoma.Methods:A total of 152 out of 355 (43%) patients randomised to ramucirumab or placebo had ⩾1 evaluable biomarker result using VEGFR2 immunohistochemistry or HER2, immunohistochemistry or FISH, of blinded baseline tumour tissue samples. Serum samples (32 patients, 9%) were assayed for VEGF-C and -D, and sVEGFR1 and 3.Results:None of the biomarkers tested were associated with ramucirumab efficacy at a level of statistical significance. High VEGFR2 endothelial expression was associated with a non-significant prognostic trend toward shorter progression-free survival (high vs low HR=1.65, 95% CI=0.84,3.23). Treatment with ramucirumab was associated with a trend toward improved survival in both high (HR=0.69, 95% CI=0.38, 1.22) and low (HR=0.73, 95% CI=0.42, 1.26) VEGFR2 subgroups. The benefit associated with ramucirumab did not appear to differ by tumoural HER2 expression.Conclusions:REGARD exploratory analyses did not identify a strong potentially predictive biomarker of ramucirumab efficacy; however, statistical power was limited.

show abstract

Section: Discussionmentioning

confidence: 97%

Biomarker analyses in REGARD gastric/GEJ carcinoma patients treated with VEGFR2-targeted antibody ramucirumab

et al. 2016

View full text Add to dashboard Cite

show abstract

“…In vitro 45-pathway profiling Gastric cancer cell lines were seeded in 24-well cell culture dishes and transfected with the 45 signaling pathway-specific reporter array panel of plasmids (SA Biosciences), as described earlier. 25 After reporter plasmid transfection, the cells were treated with 1 μM doxycycline for 36 h and then the DLR assay was performed. The percentage of pathway-specific reporter activity modulated by doxycycline in comparison with the control was plotted.…”

Section: Colony Formation Assaymentioning

confidence: 99%

Identification of the targeted therapeutic potential of doxycycline for a subset of gastric cancer patients

Pandian

Panneerpandian

Devanandan

et al. 2020

Annals of the New York Academy of Sciences

Self Cite

View full text Add to dashboard Cite

The identification of new drugs for the targeted therapy of gastric cancer remains an important need. The RAS/RAF/MEK/ERK/ELK1 signaling cascade is activated in many cancers, including gastric cancer. To identify the targetable inhibitors of the ERK/MAPK pathway, we performed a repurposing screening of a panel of antimicrobial agents in gastric cancer cells using an ERK/MAPK-driven firefly luciferase reporter assay. Multiple antibiotics were identified to inhibit ERK-mediated transcriptional activity. Among them, doxycycline showed high inhibition of ERK/MAPK-regulated transcriptional activity and the levels of ERK proteins. Doxycycline was further identified to inhibit the proliferation and the colony-and spheroid-forming potential of gastric cancer cells. By in vitro signaling pathway and genome-wide expression profiling analyses, doxycycline was identified to inhibit signaling pathways and transcriptional activities regulated by ER, Myc, E2F1, Wnt, SMAD2/3/4, Notch, and OCT4. Doxycycline was also found to activate p53-, ATF6-, NRF1/2-, and MTF1-mediated transcription and inhibit the transcription of histones, proteasomal genes, fibroblast growth factor, and other oncogenic factors. These observations show the multitargeting and targeted therapeutic features of doxycycline for a subset of gastric tumors.

show abstract

“…Regardless of EBV status, most gastric cancers have at least one aberrancy in a druggable pathway such as receptor tyrosine kinase signaling. 10 , 73 , 74 , 75 , 76 , 77 , 78 , 79 Newly identified in ‘genomically stable' gastric cancers is activated RHOA singaling via mutation of RHOA GTPase, or fusion events in RHOA inhibitors ( ARHGAPs ), broadening the opportunity to test inhibitors of the RHOA effector ROCK that are well studied in vascular biology. ROCK functions as a serine/threonine kinase impacting CDH1-mediated cell adhesion, tumor microenvironment and actin structural biology.…”

Section: Ebv-related Receptor Kinase Signalingmentioning

confidence: 99%

Genomic assays for Epstein–Barr virus-positive gastric adenocarcinoma

Gulley

2015

Exp Mol Med

View full text Add to dashboard Cite

A small set of gastric adenocarcinomas (9%) harbor Epstein–Barr virus (EBV) DNA within malignant cells, and the virus is not an innocent bystander but rather is intimately linked to pathogenesis and tumor maintenance. Evidence comes from unique genomic features of host DNA, mRNA, microRNA and CpG methylation profiles as revealed by recent comprehensive genomic analysis by The Cancer Genome Atlas Network. Their data show that gastric cancer is not one disease but rather comprises four major classes: EBV-positive, microsatellite instability (MSI), genomically stable and chromosome instability. The EBV-positive class has even more marked CpG methylation than does the MSI class, and viral cancers have a unique pattern of methylation linked to the downregulation of CDKN2A (p16) but not MLH1. EBV-positive cancers often have mutated PIK3CA and ARID1A and an amplified 9p24.1 locus linked to overexpression of JAK2, CD274 (PD-L1) and PDCD1LG2 (PD-L2). Multiple noncoding viral RNAs are highly expressed. Patients who fail standard therapy may qualify for enrollment in clinical trials targeting cancer-related human gene pathways or promoting destruction of infected cells through lytic induction of EBV genes. Genomic tests such as the GastroGenus Gastric Cancer Classifier are available to identify actionable variants in formalin-fixed cancer tissue of affected patients.

show abstract

Stratification and delineation of gastric cancer signaling by in vitro transcription factor activity profiling and integrative genomics

Cited by 11 publications

References 88 publications

Biomarker analyses in REGARD gastric/GEJ carcinoma patients treated with VEGFR2-targeted antibody ramucirumab

Biomarker analyses in REGARD gastric/GEJ carcinoma patients treated with VEGFR2-targeted antibody ramucirumab

Identification of the targeted therapeutic potential of doxycycline for a subset of gastric cancer patients

Genomic assays for Epstein–Barr virus-positive gastric adenocarcinoma

Contact Info

Product

Resources

About