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Transcription profiling of human pancreatic cancer treated with masitinib combined with standard gemcitabine chemotherapy

ABSTRACT: Masitinib is a tyrosine kinase inhibitor of c-Kit, PDGFRÎ± and Î², and to some extent Lyn of the Src kinase family. We evaluated the therapeutic potential of masitinib in vitro on human pancreatic tumour cell lines and in vivo in a mouse model of human pancreatic cancer. Experiment Overall Design: Expression patterns of masitinib tyrosine kinase targets including c-Kit, PDGFRÎ± and PDGFRÎ² were determined in four pancreatic tumour cell lines by PCR. Proliferation assays were performed with masitinib alone or in combination with gemcitabine. To determine the in vivo effects of masitinib, Nog-SCID mice were injected subcutaneously with MiaPacaÂ2 cells, randomised 28 days later and received one of the following treatments: vehicle control p.o., masitinib p.o., gemcitabine i.p., or a combination of masitinib plus gemcitabine. Additionally, the transcriptome of MiaPacaÂ2 cells for each of these conditions was determined with Affymetrix arrays.

ORGANISM(S): Homo sapiens

SUBMITTER: Pascal FINETTI

PROVIDER: E-GEOD-17987 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Novel treatment of human pancreatic cancer using masitinib combined with standard gemcitabine chemotherapy

Project description:Masitinib is a tyrosine kinase inhibitor of c-Kit, PDGFRα and β, and to some extent Lyn of the Src kinase family. We evaluated the therapeutic potential of masitinib in vitro on human pancreatic tumour cell lines and in vivo in a mouse model of human pancreatic cancer.

2009-09-05 | GSE17987 | GEO

Low endothelial cell FAK expression reduces pancreatic ductal adenocarcinoma liver metastasis after gemcitabine treatment

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2023-03-10 | PXD021542 | Pride

EMT alterations in the solute carrier landscape uncover SLC22A10/A15 imposed vulnerabilities in pancreatic cancer

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2021-10-15 | MTBLS1925 | MetaboLights

Transcription profiling of mouse liver from tumor bearing animals by TSU68 treatment

Project description:The aim of this study was to investigate the inhibitory effect of TSU68, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor beta (PDGFRÎ²) and fibroblast growth factor receptor 1 (FGFR1), on colon cancer liver metastasis and to test the hypothesis that TSU68 modulates the microenvironment in the liver before the formation of metastasis. Experiment Overall Design: The human colon cancer TK-4 was implanted orthotopically into cecal walls of 6-week-old male BALB/c nu/nu mice (Clea Japan, Tokyo, Japan). The animals were treated with TSU68 (400 mg/kg/day, twice-daily, p.o.) or vehicle from 7 days after orthotopic implantation. After one week of drug administration, livers were removed and total RNA was extracted. Experiment Overall Design: We established four different groups of mice; non-tumor-bearing and treated with vehicle alone (NT-Co), non-tumor-bearing and treated with TSU68 (NT-TSU), tumor-bearing and treated with vehicle (T-Co), and tumor-bearing and treated with TSU68 (T-TSU). NT-Co, T-Co and T-TSU group were applied to microarray analysis.

2008-10-21 | E-GEOD-11808 | biostudies-arrayexpress

Gemcitabine induced TIMP-1 attenuates therapy response and promotes tumour growth and liver metastasis in pancreatic cancer

Project description:Gemcitabine constitutes one of the backbones for chemotherapy treatment in pancreatic ductal adenocarcinoma (PDAC) but patients often show poor or complete lack of response to this agent. Molecular markers downstream of Gemcitabine treatment in pre-clinical models may provide an insight into resistance mechanisms. We identified potential secretory biomarkers of Gemcitabine resistance (response) in the transgenic KRasG12D; Trp53R172H; Pdx-1 Cre (KPC) mouse model of PDAC using cytokine arrays. We validated the oncogenic role of the cytokine tissue inhibitor of matrix metalloproteinases 1 (TIMP-1) in primary pancreatic tumours and metastasis using both in vitro techniques and animal models. We identified potential pathways affected downstream of TIMP-1 using the Illumina Human H12 array. Our findings were validated in both primary and metastatic models of pancreatic cancer. Gemcitabine increases inflammatory cytokines including TIMP-1 in the KPC mouse model. TIMP-1 is upregulated in patients with pancreatic intraepithelial neoplasias grade 3 and PDAC lesions relative to matched normal pancreatic tissue. Additionally, we demonstrate that TIMP-1 plays a role in tumour proliferation and angiogenesis, while inhibition resensitises to gemcitabine and radiotherapy. Strikingly, serum TIMP-1 levels support the formation of liver metastasis through the recruitment of immunosuppressive cell populations, such as CD11b+Gr1+ myeloid cells and CD4+CD25+FOXP3+ Tregs to the hepatic microenvironment. Gemcitabine treatment results in upregulation of the pro-tumourigenic/pro-metastatic cytokine TIMP-1, which partially explains the therapeutic resistance and poor responses to this therapy in PDAC. Our study provides a rationale for the development and testing of TIMP-1 specific inhibitors in addition to chemo/radiotherapy.

2017-08-08 | GSE94891 | GEO

mRNA-seq of gemcitabine resistant pancreatic cancer cell line subclones derived from BxPC3

Project description:We generated gemcitabine resistant subclones from the human pancreatic cancer cell line BxPC3 using chronic low dose exposure to gemcitabine. Three gemcitabine resistant subclones (BxGR-80C, BxGR-120C and BxGR-360C) were sequenced in addition to BxPC3 cells.

2021-12-21 | E-MTAB-11186 | biostudies-arrayexpress

The miRNA profiling in PANC-1, PANC-1 GEM 100 and PANC-1 GEM1500 cells

Project description:Gemcitabine has been a first-line therapeutic agent for pancreatic ductal adenocarcinoma (PDAC) pancreatic cancer; however, acquisition of resistance to gemcitabine remains a major challenge. We analyzed miRNAs expression profiles by array-based miRNAs analysis between gemcitabine–resistant (PANC-1/GEM) and parental PANC-1 cells.

2016-12-31 | GSE79234 | GEO

A network-based strategy for prioritizing hits from chemical screening data by leveraging genetic, epigenetic and transcriptional datasets

Project description:Small molecule screens are widely used to prioritize compounds for development of pharmaceuticals and to reveal pathways altered in biological processes. However, interpreting the results of these screens is very challenging since in almost all cases, the compounds are highly promiscuous. Here we present a network-based strategy for analyzing molecular screening data. We report a screen for kinase inhibitors that synergize with gemcitabine, the first-line chemotherapy treatment for pancreatic cancer. The eight kinase inhibitors that emerge from the screen target a total of 140 kinases, and these kinases show little overlap with previously detected genetic modifiers of gemcitabine toxicity. Using the SAMNet algorithm, we link the chemical and genetic modifiers of gemcitabine toxicity to transcriptional and epigenetic changes induced by gemcitabine that we measure using DNaseI-Seq and RNA-Seq. SAMNet uses a constrained optimization algorithm to connect genes from these complementary datasets through a small set of protein-protein and protein-DNA interactions. The resulting network is able to recapitulate known gemcitabine response pathways including DNA damage repair, control of cellular growth and the EMT pathway. We query the network downstream of putative kinase inhibitor targets and in addition to identifying known gemcitabine synergizers STAT3, NFKB2 and AKT1, we propose novel candidate targets for gemcitabine chemoresistance, including ETS transcription factors (ELK1, ELK3) and the adaptor protein NCK1. Our work suggests that a subset of the “off-target kinases” are directly involved in the cellular response to gemcitabine by modulating the activity of known and proposed chemosensitizing genes.

2017-10-31 | GSE70810 | GEO

RNA-seq data of nasopharyngeal carcinoma (NPC) cell and GO-PEG_erlotinib treatment

Project description:graphene oxide (GO) is found to be a promising novel anti-cancer drug carrier. Erlotinib, a tyrosine kinase inhibitor (TKI) acting on the epidermal growth factor receptor (EGFR), has been proved for locally advanced or metastatic non-small cell lung cancer (NSCLC) and in combination with gemcitabine for locally advanced or metastatic pancreatic cancer in 2004, but its study in nasopharyngeal carcinoma (NPC) is still limited. We designed functionalized GO, polyethylene glycol-coated GO (GO-PEG), as drug carriers, which was loaded with erlotinib and showed promising anticancer effect on NPC cells. Our results showed that GO-PEG-erlotinib effectively suppressed NPC cell proliferation, migration, and invasion, likely by several mechanisms. GO-PEG-erlotinib may be the potential therapeutic agents for treating NPC in the future.

2021-12-27 | GSE151195 | GEO

Expression profiling of budding cells in colorectal cancer suggests an EMT-like phenotype and molecular subtype switching

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2017-02-04 | E-MTAB-4065 | biostudies-arrayexpress

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