Objectif For > 70% of cholangiocarcinoma (CCA) patients, no curative treatment is available at time of diagnosis and they proceed directly to palliative chemotherapy with virtually 0% surviving at 5 years. Breaking overall cancer trends, CCA mortality rates are escalating among both sexes in the EU, exacerbating this clinical demographic of intractable patients. Recently, a deluge of deep sequencing studies have identified recurrent mutations in epigenetic enzymes in CCA, prompting a turning point in our view of the molecular architecture of this devastating malignancy. Unlike traditional mutations, epigenetic lesions or ‘epimutations’ are intrinsically reversible and, therefore, may comprise an optimal Achilles heel to target for therapeutic benefit. However, to streamline epigenome-driven therapy to the clinic, we first need to clarify molecular and cellular responses to epigenetic manipulation in different CCA models. Accordingly, I have 3 specific objectives of this proposal: i) I plan to carry out a comprehensive in vitro epi-drug screen to determine which enzymatic targets have the greatest anti-neoplastic activity; from this, ii) I will characterize the epigenomic changes that underpin such phenotypic rescue; finally, iii) I will compare the therapeutic effects of the top global-acting epi-drug versus target-specific epigenetic editing (Epi-CRISPR) of the most recurrent epimutation in vivo. Accomplishment of these objectives will improve our understanding of cholangiocarcinogenesis and also address the unmet clinical need for novel therapeutic targets in this cancer demographic with abysmal prognosis. The project will be supervised by Dr. Jesper Andersen, a world-leading expert in hepatobiliary cancer genomics, and will draw extensively on his expansive patient bio- and data-bank. Through this work, I aim to broaden my scientific expertise (including technical and transferable skills) and to establish myself as an independent researcher in translational epigenomics. Champ scientifique medical and health sciencesbasic medicinepharmacology and pharmacydrug discoverynatural sciencesbiological sciencesgeneticsmutationmedical and health sciencesclinical medicineoncologynatural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymesnatural sciencesbiological sciencesgeneticsepigenetics Programme(s) H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions Main Programme H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility Thème(s) MSCA-IF-2015-EF - Marie Skłodowska-Curie Individual Fellowships (IF-EF) Appel à propositions H2020-MSCA-IF-2015 Voir d’autres projets de cet appel Régime de financement MSCA-IF-EF-ST - Standard EF Coordinateur KOBENHAVNS UNIVERSITET Contribution nette de l'UE € 200 194,80 Adresse Norregade 10 1165 Kobenhavn Danemark Voir sur la carte Région Danmark Hovedstaden Byen København Type d’activité Higher or Secondary Education Establishments Liens Contacter l’organisation Opens in new window Site web Opens in new window Participation aux programmes de R&I de l'UE Opens in new window Réseau de collaboration HORIZON Opens in new window Coût total € 200 194,80