A systems biology perspective on cholangiocellular carcinoma development: Focus on MAPK-signaling and the extracellular environment

Wang, Chunxia; Maass, T; Krupp, Markus; Thieringer, F.; Strand, Susanne; Wörns, Marcus A.; Barreiros, A. P.; Galle, Peter R.; Teufel, Andreas

doi:10.1016/j.jhep.2009.01.024

Cited by 18 publications

(15 citation statements)

References 38 publications

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“…The RAF/MEK/ERK signalling pathway is involved in the regulation of normal cell proliferation, survival, and differentiation, and this pathway is frequently aberrantly upregulated in a wide number of cancers including cholangiocarcinoma (Yoon et al , 2004; Roberts and Der, 2007; Schmitz et al , 2007; Wang et al , 2009). Alterations in this pathway have been reported in up to 35% and 55% of intrahepatic and extrahepatic cholangiocarcinomas, respectively (Churi et al , 2014).…”

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confidence: 99%

The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma

et al. 2017

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Background:Cholangiocarcinoma is an aggressive malignancy with limited therapeutic options. MEK inhibition and antiangiogenic therapies have individually shown modest activity in advanced cholangiocarcinoma, whereas dual inhibition of these pathways has not been previously evaluated. We evaluated the safety and efficacy of combination therapy with the oral VEGF receptor tyrosine kinase inhibitor pazopanib plus the MEK inhibitor trametinib in patients with advanced cholangiocarcinoma.Methods:In this open-label, multicentre, single-arm trial, adults with advanced unresectable cholangiocarcinoma received pazopanib 800 mg daily and trametinib 2 mg daily until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) with secondary end points including overall survival (OS), response rate, and disease control rate (DCR).Results:A total of 25 patients were enrolled and had received a median of 2 prior systemic therapies (range 1–7). Median PFS was 3.6 months (95% CI: 2.7–5.1) and the 4-month PFS was 40% (95% CI: 24.7–64.6%). There was a trend towards increased 4-month PFS as compared with the prespecified null hypothesised 4-month PFS of 25%, but this difference did not reach statistical significance (P=0.063). The median survival was 6.4 months (95% CI: 4.3–10.2). The objective response rate was 5% (95% CI: 0.13–24.9%) and the DCR was 75% (95% CI: 51%, 91%). Grade 3/4 adverse events attributable to study drugs were observed in 14 (56%) and included thrombocytopenia, abnormal liver enzymes, rash, and hypertension.Conclusions:Although the combination of pazopanib plus trametinib had acceptable toxicity with evidence of clinical activity, it did not achieve a statistically significant improvement in 4-month PFS over the prespecified null hypothesised 4-month PFS.

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confidence: 99%

The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma

et al. 2017

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“…Thus they must not only be investigated focussing on individual, potentially key regulatory genes but also with respect to underlying genetic clusters and networks [7,20-22]. However, to investigate these complex molecular interactions, data resources providing a comprehensive collection of all genes involved in the development of the diseases are urgently needed.…”

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confidence: 99%

Library of molecular associations: curating the complex molecular basis of liver diseases

et al. 2010

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BackgroundSystems biology approaches offer novel insights into the development of chronic liver diseases. Current genomic databases supporting systems biology analyses are mostly based on microarray data. Although these data often cover genome wide expression, the validity of single microarray experiments remains questionable. However, for systems biology approaches addressing the interactions of molecular networks comprehensive but also highly validated data are necessary.ResultsWe have therefore generated the first comprehensive database for published molecular associations in human liver diseases. It is based on PubMed published abstracts and aimed to close the gap between genome wide coverage of low validity from microarray data and individual highly validated data from PubMed. After an initial text mining process, the extracted abstracts were all manually validated to confirm content and potential genetic associations and may therefore be highly trusted. All data were stored in a publicly available database, Library of Molecular Associations http://www.medicalgenomics.org/databases/loma/news, currently holding approximately 1260 confirmed molecular associations for chronic liver diseases such as HCC, CCC, liver fibrosis, NASH/fatty liver disease, AIH, PBC, and PSC. We furthermore transformed these data into a powerful resource for molecular liver research by connecting them to multiple biomedical information resources.ConclusionTogether, this database is the first available database providing a comprehensive view and analysis options for published molecular associations on multiple liver diseases.

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“…As exemplified in the aforementioned studies of moleculartargeted therapies, global gene expression screening might not only unveil the molecular pathways affected by specific drugs but may also help to define the pathogenic molecular effectors that need to be targeted by appropriate drugs. Following this approach, Wang et al 91 extracted all PubMedpublished genetic associations for the development of cholangiocellular carcinoma and integrated related microarray data, demonstrating that the MAPK pathway was a relevant therapeutic target, and that sorafenib, a selective Raf kinase inhibitor, could be a potential treatment. Another approach for identifying promising therapeutic targets and developing new therapies involves determining the mode of action of empirically used drugs.…”

Section: Applications Of Array-based Pharmacogenomics In Identifying mentioning

confidence: 99%

Array-based pharmacogenomics of molecular-targeted therapies in oncology

et al. 2012

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The advent of microarrays over the past decade has transformed the way genome-wide studies are designed and conducted, leading to an unprecedented speed of acquisition and amount of new knowledge. Microarray data have led to the identification of molecular subclasses of solid tumors characterized by distinct oncogenic pathways, as well as the development of multigene prognostic or predictive models equivalent or superior to those of established clinical parameters. In the field of molecular-targeted therapy for cancer, in particular, the application of array-based methodologies has enabled the identification of molecular targets with 'key' roles in neoplastic transformation or tumor progression and the subsequent development of targeted agents, which are most likely to be active in the specific molecular setting. Herein, we present a summary of the main applications of whole-genome expression microarrays in the field of molecular-targeted therapies for solid tumors and we discuss their potential in the clinical setting. An emphasis is given on deciphering the molecular mechanisms of drug action, identifying novel therapeutic targets and suitable agents to target them with, and discovering molecular markers/signatures that predict response to therapy or optimal drug dose for each patient.

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A systems biology perspective on cholangiocellular carcinoma development: Focus on MAPK-signaling and the extracellular environment

Cited by 18 publications

References 38 publications

The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma

The oral VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced cholangiocarcinoma

Library of molecular associations: curating the complex molecular basis of liver diseases

Array-based pharmacogenomics of molecular-targeted therapies in oncology

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