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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, 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. Experiment Overall Design: Expression patterns of masitinib tyrosine kinase targets including c-Kit, PDGFRα and PDGFRβ 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 MiaPaca2 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 MiaPaca2 cells for each of these conditions was determined with Affymetrix arrays.

ORGANISM(S): Homo sapiens

SUBMITTER: FINETTI Pascal

PROVIDER: S-ECPF-GEOD-17987 | biostudies-other |

REPOSITORIES: biostudies-other

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

Project description: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.

2009-09-17 | E-GEOD-17987 | biostudies-arrayexpress

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

Prognostic nomogram for nonresectable pancreatic cancer treated with gemcitabine-based chemotherapy.

Project description:BACKGROUND: A nomogram is progressively being used as a useful predictive tool for cancer prognosis. A nomogram to predict survival in nonresectable pancreatic cancer treated with chemotherapy has not been reported. METHODS: Using prospectively collected data on patients with nonresectable pancreatic cancer receiving gemcitabine-based chemotherapy at five Japanese hospitals, we derived a predictive nomogram and internally validated it using a concordance index and calibration plots. RESULTS: In total, 531 patients were included between June 2001 and February 2013. The American Joint Committee on Cancer (AJCC) TNM stages were III and IV in 204 and 327 patients, respectively. The median survival time of the total cohort was 11.3 months. A nomogram was generated to predict survival probabilities at 6, 12, and 18 months and median survival time, based on the following six variables: age; sex; performance status; tumour size; regional lymph node metastasis; and distant metastasis. The concordance index of the present nomogram was higher than that of the AJCC TNM staging system at 12 months (0.686 vs 0.612). The calibration plots demonstrated good fitness of the nomogram for survival prediction. CONCLUSIONS: The present nomogram can provide valuable information for tailored decision-making early after the diagnosis of nonresectable pancreatic cancer.

| S-EPMC3992497 | biostudies-other

Timing of chemotherapy-induced neutropenia: the prognostic factor in advanced pancreatic cancer patients treated with gemcitabine / gemcitabine-based chemotherapy.

Project description:Chemotherapy-induced neutropenia (CIN) was reported to be a predictor of better survival in several cancers. The objective of our study is to evaluate the relationship between the timing (onset) of CIN and prognosis. Between June 2008 and June 2015, 134 patients with confirmed advanced pancreatic cancer received at least one cycle of gemcitabine / gemcitabine-based chemotherapy as first-line chemotherapy were eligible for assessment. Timing of CIN was categorized into early onset and non-early onset CIN group. The end of cycle 2 was the cutoff to differentiate early onset or non-early onset. The correlation between timing of CIN with survival was analyzed by Kaplan-Meier method and Cox proportional hazards model. Median overall survival (OS) was 8.05 months (95% CI: 5.97-10.13) for patients with early onset CIN compared with 5.82 months (95% CI: 5.00-6.63) for patients without early-onset neutropenia (P = 0.022). Multivariate analysis proved that timing of CIN was an independent prognostic factor, hazard ratios of death was 0.696 (95% CI: 0.466-0.938) for patients with early onset CIN. In conclusion, timing of CIN is an independent predictor of prognosis in patients with advanced pancreatic cancer undergoing gemcitabine / gemcitabine based chemotherapy. Early-onset CIN predicts better survival.

| S-EPMC5630440 | biostudies-literature

Masitinib combined with standard gemcitabine chemotherapy: in vitro and in vivo studies in human pancreatic tumour cell lines and ectopic mouse model.

Project description:BACKGROUND: Tyrosine kinases are attractive targets for pancreatic cancer therapy because several are over-expressed, including PDGFRalpha/beta, FAK, Src and Lyn. A critical role of mast cells in the development of pancreatic cancer has also been reported. Masitinib is a tyrosine kinase inhibitor that selectively targets c-Kit, PDGFRalpha/beta, Lyn, and to a lesser extent the FAK pathway, without inhibiting kinases of known toxicities. Masitinib is particularly efficient in controlling the proliferation, differentiation and degranulation of mast cells. This study evaluates the therapeutic potential of masitinib in pancreatic cancer, as a single agent and in combination with gemcitabine. METHODOLOGY/FINDINGS: Proof-of-concept studies were performed in vitro on human pancreatic tumour cell lines and then in vivo using a mouse model of human pancreatic cancer. Molecular mechanisms were investigated via gene expression profiling. Masitinib as a single agent had no significant antiproliferative activity while the masitinib/gemcitabine combination showed synergy in vitro on proliferation of gemcitabine-refractory cell lines Mia Paca2 and Panc1, and to a lesser extent in vivo on Mia Paca2 cell tumour growth. Specifically, masitinib at 10 microM strongly sensitised Mia Paca2 cells to gemcitabine (>400-fold reduction in IC(50)); and moderately sensitised Panc1 cells (10-fold reduction). Transcriptional analysis identified the Wnt/beta-catenin signalling pathway as down-regulated in the cell lines resensitised by the masitinib/gemcitabine combination. CONCLUSIONS: These data establish proof-of-concept that masitinib can sensitise gemcitabine-refractory pancreatic cancer cell lines and warrant further in vivo investigation. Indeed, such an effect has been recently observed in a phase 2 clinical study of patients with pancreatic cancer who received a masitinib/gemcitabine combination.

| S-EPMC2832006 | biostudies-literature

Transcription profiling by array of human HhAntag-treated pancreatic xenograft tumors

Project description:Four vehicle-treated and four HhAntag-treated pancreatic xenograft tumors were profiled for gene expression changes using Affymetrix U133 Plus 2.0 and Affymetrix Mouse Genome 430 2.0 arrays. Keywords: comparative gene expression, hedgehog, hh A primary human pancreatic tumor xenograft (1051178-A) was established by direct implantation of surgical material into female CD1 nu/nu mice of 6-8 weeks of age. Tumors were serially passaged into larger cohorts of mice for efficacy testing and subsequently distributed into tumor volume-matched cohorts upon tumors reaching between 200 to 350 mm3. HhAntag was resuspended in 0.5% methyl-cellulose, 0.2% Tween-80 (MCT) and administered orally twice daily at 75 mg/kg from a 10 mg/ml suspension. MCT alone served as vehicle control. Tumor xenografts (4/group) were excised following 21 days of dosing and RNA was extracted. Preparation of complementary RNA, Human Genome U133 Plus 2.0 array and Mouse Genome 430 2.0 array hybridizations, and subsequent data analysis were carried out using Affymetrix protocols, with signal intensities being determined by the MAS5.0 algorithm.

| S-ECPF-GEOD-11981 | biostudies-other

Predictive role of human equilibrative nucleoside transporter 1 in patients with pancreatic cancer treated by curative resection and gemcitabine-only adjuvant chemotherapy.

Project description:The predictive roles of human equilibrative nucleoside transporter 1 (hENT-1) in patients who undergo curative resection and adjuvant chemotherapy with gemcitabine alone have not been established. The present study retrospectively analyzed the clinical data from 101 consecutive patients who underwent curative resection and who received gemcitabine adjuvant chemotherapy for the treatment of pancreatic cancer at Kanagawa Cancer Center (Yokohama, Japan) between 2005 and 2014. The associations between the hENT-1 status and the survival and clinicopathological features of the patients were investigated. Of the 101 patients, 60 patients (59.4%) had high levels of hENT-1 expression. A significant association was observed between hENT-1 status and sex; however, for all the other clinicopathological parameters, including tumor and node stages, no differences were observed between the high and low hENT-1 expression groups. The median follow-up period of the present study was 67.3 months. Between the high and low hENT-1 expression groups, there was a statistically significant difference in the 5-year overall survival (OS) rates following surgery (20.6 and 8.9%, respectively; P=0.019). In addition, a significant difference was observed in the recurrence-free survival (RFS) rates at 5 years following surgery (P=0.049). hENT-1 status was one of the important predictive factors for OS and RFS in patients with pancreatic cancer who underwent curative resection followed by adjuvant chemotherapy with gemcitabine. Adjuvant chemotherapy with gemcitabine alone may be insufficient, particularly in patients with certain relevant risk factors.

| S-EPMC5494679 | biostudies-other

A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea.

Project description:BackgroundThis phase III trial compared the efficacy and safety of gemcitabine plus capecitabine (GemCap) versus single-agent gemcitabine (Gem) in advanced pancreatic cancer as first-line chemotherapy.MethodsA total of 214 advanced pancreatic cancer patients were enrolled from 16 hospitals in South Korea between 2007 and 2011. Patients were randomly assigned to receive GemCap (oral capecitabine 1660?mg/m plus Gem 1000?mg/m by 30-minute intravenous infusion weekly for 3 weeks followed by a 1-week break every 4 weeks) or Gem (by 30-minute intravenous infusion weekly for 3 weeks every 4 weeks).ResultsMedian overall survival (OS) time, the primary end point, was 10.3 and 7.5 months in the GemCap and Gem arms, respectively (P?=?0.06). Progression-free survival was 6.2 and 5.3 months in the GemCap and Gem arms, respectively (P?=?0.08). GemCap significantly improved overall response rate compared with Gem alone (43.7% vs 17.6%; P?=?0.001). Overall frequency of grade 3 or 4 toxicities was similar in each group. Neutropenia was the most frequent grade 3 or 4 toxicity in both groups.ConclusionGemCap failed to improve OS at a statistically significant level compared to Gem treatment. This study showed a trend toward improved OS compared to Gem alone. GemCap and Gem both exhibited similar safety profiles.

| S-EPMC5228666 | biostudies-literature

HMGA-targeted phosphorothioate DNA aptamers increase sensitivity to gemcitabine chemotherapy in human pancreatic cancer cell lines.

Project description:Elevated high mobility group A (HMGA) protein expression in pancreatic cancer cells is correlated with resistance to the chemotherapy agent gemcitabine. Here, we demonstrate use of HMGA-targeted AT-rich phosphorothioate DNA (AT-sDNA) aptamers to suppress HMGA carcinogenic activity. Cell growth of human pancreatic cancer cells (AsPC-1 and Miapaca-2) transfected with AT-sDNA were monitored after treatment with gemcitabine. Significant increases in cell death in AT-sDNA transfected cells compared to non-AT-rich sDNA treated cells were observed in both cell lines. The data indicate the potential use of HMGA targeted DNA aptamers to enhance chemotherapy efficacy in pancreatic cancer treatment.

| S-EPMC3914216 | biostudies-literature

Proteomic Analysis of Combined Gemcitabine and Birinapant in Pancreatic Cancer Cells.

Project description:Pancreatic cancer is characterized by mutated signaling pathways and a high incidence of drug resistance. Comprehensive, large-scale proteomic analysis can provide a system-wide view of signaling networks, assist in understanding drug mechanisms of action and interactions, and serve as a useful tool for pancreatic cancer research. In this study, liquid chromatography-mass spectrometry-based proteomic analysis was applied to characterize the combination of gemcitabine and birinapant in pancreatic cancer cells, which was shown previously to be synergistic. A total of 4069 drug-responsive proteins were identified and quantified in a time-series proteome analysis. This rich dataset provides broad views and accurate quantification of signaling pathways. Pathways relating to DNA damage response regulations, DNA repair, anti-apoptosis, pro-migration/invasion were implicated as underlying mechanisms for gemcitabine resistance and for the beneficial effects of the drug combination. Promising drug targets were identified for future investigation. This study also provides a database for systems mathematical modeling to relate drug effects and interactions in various signaling pathways in pancreatic cancer cells.

| S-EPMC5827530 | biostudies-literature

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