A Novel Strategy for Combination of Clofarabine and Pictilisib is Synergistic in Gastric Cancer
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE174288 | GEO | 2021/11/01
REPOSITORIES: GEO
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Project description:A Novel Strategy for Combination of Clofarabine and Pictilisib is Synergistic in Gastric Cancer
| PRJNA729107 | ENA
Project description:Ornithogalum is one of the therapeutic formulation used in homeopathic treatments. It is specifically used in the treatment for gastric and duodenal ulcerations. Towards understanding the anticancer mechanism, we investigated the genome-wide mRNA changes upon treating AGS Gastric Cancer cells with Ornithogalum. We observed that totally 707 genes were significantly regulated upon Ornithogalum Treatment, among them 246 genes were upregulated and 461 genes were downregulated. The results provide insight into molecular implication and gene level expression of AGS upon treatment with Ornithogalum. Total RNA was isolated from AGS gastric cancer cells treated with 0.01% of ornithogalum and ethanol control and profiled using Affymetrix Human Gene 1.0 ST Array (HuGene-1_0-st).
2014-04-01 | E-GEOD-54658 | biostudies-arrayexpress
Project description:Abstract BACKGROUND: The basal-like breast cancer (BLBC) subtype is characterized by positive staining for basal mammary epithelial cytokeratin markers, lack of hormone receptor and HER2 expression, and poor prognosis with currently no approved molecularly-targeted therapies. The oncogenic signaling pathways driving basal-like tumorigenesis are not fully elucidated. METHODS: One hundred sixteen unselected breast tumors were subjected to integrated analysis of phosphoinositide 3-kinase (PI3K) pathway related molecular aberrations by immunohistochemistry, mutation analysis, and gene expression profiling. Incidence and relationships between molecular biomarkers were characterized. Findings for select biomarkers were validated in an independent series. Synergistic cell killing in vitro and in vivo tumor therapy was investigated in breast cancer cell lines and mouse xenograft models, respectively. RESULTS: Sixty-four % of cases had an oncogenic alteration to PIK3CA, PTEN, or INPP4B; when including upstream kinases HER2 and EGFR, 75 % of cases had one or more aberration including 97 % of estrogen receptor (ER)-negative tumors. PTEN-loss was significantly associated to stathmin and EGFR overexpression, positivity for the BLBC markers cytokeratin 5/14, and the BLBC molecular subtype by gene expression profiling, informing a potential therapeutic combination targeting these pathways in BLBC. Combination treatment of BLBC cell lines with the EGFR-inhibitor gefitinib plus the PI3K pathway inhibitor LY294002 was synergistic, and correspondingly, in an in vivo BLBC xenograft mouse model, gefitinib plus PI3K-inhibitor PWT-458 was more effective than either monotherapy and caused tumor regression. CONCLUSIONS: Our study emphasizes the importance of PI3K/PTEN pathway activity in ER-negative and basal-like breast cancer and supports the future clinical evaluation of combining EGFR and PI3K pathway inhibitors for the treatment of BLBC. Gene expression profiles were generated for 95 breast tumors using Agilent Human 44K v5 microarrays following the manufacturer protocol. Stratagene Universal Human Reference RNA was used as the common control sample.
2016-08-21 | E-GEOD-74667 | biostudies-arrayexpress
Project description:Ornithogalum is one of the therapeutic formulation used in homeopathic treatments. It is specifically used in the treatment for gastric and duodenal ulcerations. Towards understanding the anticancer mechanism, we investigated the genome-wide mRNA changes upon treating AGS Gastric Cancer cells with Ornithogalum. We observed that totally 707 genes were significantly regulated upon Ornithogalum Treatment, among them 246 genes were upregulated and 461 genes were downregulated. The results provide insight into molecular implication and gene level expression of AGS upon treatment with Ornithogalum.
2014-04-01 | GSE54658 | GEO
Project description:Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a tumor suppressor that negatively regulates cell survival and proliferation by antagonizing phosphatidylinositol 3-kinase(PI3K)/protein kinase B(PKB/Akt) signaling. Loss of heterozygosity (LOH) of PTEN, reduced expression of PTEN and overexpression of phosphorylated Akt are frequently found in human gastric cancer, and their changes correlate with tumor progression and prognosis. Previous studies have shown that the deregulated miRNAs in human gastric cancer play important roles in gastric cancer cell proliferation, apoptosis and inflammation. However, miRNAs downstream PTEN/Akt signaling is poorly investigated. To clarify whether PTEN is involved in gastric tumorigenesis, we have generated a gastric epithelium specific PTEN knockout mouse which exhibited gastric tumor formation with enhanced cell proliferation.So the objectives of the microarray experiment were to, a) screen miRNAs which might be regulated by PTEN/Akt signaling by comparing the miRNA expression profiles between PTEN deficient and control gastric epithelia. 2) explore the microRNA mechanism involved in gastric cell proliferation and gastric tumorigenesis. miRNA profiling of mouse gastric epithelium,comparing Pten mutant mouse with controls. 4 samples. Experiments in 2 different time point, 20 days and 60 days after birth, 2 Biological replicates. Mutant tissue vs. controls from mixture of 3-4 mouse.
2013-09-02 | E-GEOD-27047 | biostudies-arrayexpress
Project description:Highlights • Drug sensitivity testing identified novel drugs like clofarabine effective in treating gastric cancer.• mRNA sequencing can be used to identify agents with synergistic activity to a reference compound.• Pictilisib sensitizes gastric cancer to clofarabine treatment through AKT inhibition.• The combination of clofarabine and pictilisib inhibits tumor growth in cell lines and PDX models. Gastric cancer (GC) is frequently characterized by resistance to standard chemotherapeutic regimens and poor clinical outcomes. We aimed to identify a novel therapeutic approach using drug sensitivity testing (DST) and our computational SynerySeq pipeline. DST of GC cell lines was performed with a library of 215 Federal Drug Administration (FDA) approved compounds and identified clofarabine as a potential therapeutic agent. RNA-sequencing (RNAseq) of clofarabine treated GC cells was analyzed according to our SynergySeq pipeline and identified pictilisib as a potential synergistic agent. Clonogenic survival and Annexin V assays demonstrated increased cell death with clofarabine and pictilisib combination treatment (P<0.01). The combination induced double strand breaks (DSB) as indicated by phosphorylated H2A histone family member X (γH2AX) immunofluorescence and western blot analysis (P<0.01). Pictilisib treatment inhibited the protein kinase B (AKT) cell survival pathway and promoted a pro-apoptotic phenotype as evidenced by quantitative real time polymerase chain reaction (qRT-PCR) analysis of the B-cell lymphoma 2 (BCL2) protein family members (P<0.01). Patient derived xenograft (PDX) data confirmed that the combination is more effective in abrogating tumor growth with prolonged survival than single-agent treatment (P<0.01). The novel combination of clofarabine and pictilisib in GC promotes DNA damage and inhibits key cell survival pathways to induce cell death beyond single-agent treatment.
| S-EPMC8571525 | biostudies-literature
Project description:This study was conducted to identify transcriptional profiles predictive of a clinical response of metastatic gastric cancer patients to cisplatin and fluorouracil (CF) combination chemotherapy. Endoscopic biopsy samples were collected from CF-treated metastatic gastric cancer patients prior to therapy and following the development of resistance to therapy.
2011-06-01 | E-GEOD-14208 | biostudies-arrayexpress
Project description:BACKGROUND & AIMS: Gastric cancer is the second most frequent cause of death from cancer in the world, diffuse-type gastric cancer (DGC) exhibiting a poor prognosis. Germline mutations of CDH1, encoding E-cadherin, have been reported in hereditary DGCs, and genetic and/or epigenetic alterations of CDH1 are frequently detected in sporadic DGCs. Genetic alterations of TP53 are also frequently found in DGCs. To examine the synergistic effect of loss of E-cadherin and p53 on gastric carcinogenesis, we established a mouse line in which E-cadherin and p53 are specifically inactivated in the stomach parietal cell lineage. METHODS: We crossed Atp4b-Cre mice with Cdh1loxP/loxP and Trp53loxP/loxP mice, and examined the gastric phenotype of Atp4b-Cre+;Cdh1loxP/loxP;Trp53loxP/loxP mice. RESULTS: Non-polarization of E-cadherin-negative parietal cells and proton pump-negative atypical foci were observed in the transgenic mice. Intramucosal cancers and invasive cancers composed of poorly differentiated carcinoma cells and signet ring cells, which were histologically very similar to those in humans, were found from 6 and 9 months, respectively. Fatal DGCs developed at 100% penetrance within a year, frequently metastasized to lymph nodes, and had tumorigenic activity in immunodeficient mice. Gene expression profiling analyses also revealed that DGCs in the E-cadherin/p53-deficient mice resembled human DGCs. CONCLUSIONS: Our mouse line is the first genetically modified mouse model of DGC and very useful for clarifying the mechanism underlying gastric carcinogenesis, and provides a new approach to the treatment and prevention of DGC because of morphological and biochemical similarities with human DGC. Two-condition experiment, Gastric cancer vs. normal gastric mucosal tissues. Biological replicates: pooled control sample from five normal gastric mucosal tissues, three replicates from diffuse-type gastric cancer.
2011-12-04 | E-GEOD-25302 | biostudies-arrayexpress
Project description:Gastric cancer is one of the most common causes of cancer-related death worldwide, and the molecular mechanisms involved in gastric carcinogenesis are still not fully understood. To gain molecular understanding of carcinogenesis, progression, and diversity of gastric cancer, 111 human gastric cancer tissues and 21 noncancerous gastric tissues were analyzed by high-density oligonucleotide microarray in this study. These results provide not only a new molecular basis for understanding biological properties of gastric cancer, but also useful resources for future development of therapeutic targets and diagnostic markers for gastric cancer.
2017-01-15 | GSE54129 | GEO
Project description:Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a tumor suppressor that negatively regulates cell survival and proliferation by antagonizing phosphatidylinositol 3-kinase(PI3K)/protein kinase B(PKB/Akt) signaling. Loss of heterozygosity (LOH) of PTEN, reduced expression of PTEN and overexpression of phosphorylated Akt are frequently found in human gastric cancer, and their changes correlate with tumor progression and prognosis. Previous studies have shown that the deregulated miRNAs in human gastric cancer play important roles in gastric cancer cell proliferation, apoptosis and inflammation. However, miRNAs downstream PTEN/Akt signaling is poorly investigated. To clarify whether PTEN is involved in gastric tumorigenesis, we have generated a gastric epithelium specific PTEN knockout mouse which exhibited gastric tumor formation with enhanced cell proliferation.So the objectives of the microarray experiment were to, a) screen miRNAs which might be regulated by PTEN/Akt signaling by comparing the miRNA expression profiles between PTEN deficient and control gastric epithelia. 2) explore the microRNA mechanism involved in gastric cell proliferation and gastric tumorigenesis.
2013-09-02 | GSE27047 | GEO