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Characterization and implications of DNA damage response in liver cancer

Objective

Cholangiocarcinoma (CCA) is a devastating type of liver cancer that presents late, is difficult to diagnose and associated with a high mortality. Although worldwide the epidemiological trend is mixed, in the EU it has been steadily increasing for the last decade. Treatment is limited to tumor resection, which is not applicable in the vast majority of cases. The lack of any approved chemotherapy-based treatment is partially due to the poor understanding of the molecular mechanisms involved in the response to these drugs. Taking advantage of the comprehensive panel of established and primary CCA cell lines in the host PI’s lab and my expertise on the DNA damage response (DDR) and repair field, my proposal offers a new approach in this scenario by characterizing the DDR of CCA cells. This study will be focused on the DDR-related chromatin remodeling SWI/SNF complex. In recent works, mutations in this family of proteins were identified in 47% of all CCA cases analyzed through whole exome sequencing, hence providing a relevant rationale in studying this complex. First, I will identify candidate markers of all known components of the SWI/SNF complex, based on RNAi high-throughput analysis. I will then perform direct and quantitative measurements of the DNA repair activity in CCA cells, specifically related to homologous recombination repair (HR) by rapid and sensitive reporter assays. And lastly, I will determine the proteome dynamics in the CCA context. There are two exclusive novelties on this approach: (1) the described novel methods will be employed in the Hepatology field for the first time; and (2) the use of primary CCA cells will enable me to directly compare observations in culture with clinical outcome. This proposal will not only contribute to the understanding of a limited understood area in liver cancer, but also holds great promises for future clinical use, where DDR-based drugs are the clinical mainstay

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Programme(s)

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Topic(s)

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Funding Scheme

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MSCA-IF-EF-ST - Standard EF

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Call for proposal

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(opens in new window) H2020-MSCA-IF-2014

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Coordinator

KOBENHAVNS UNIVERSITET
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 200 194,80
Address
NORREGADE 10
1165 KOBENHAVN
Denmark

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Region
Danmark Hovedstaden Byen København
Activity type
Higher or Secondary Education Establishments
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

€ 200 194,80
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