To investigate the therapeutic potential of epigenome-targeted therapy for CCA, I treated 10 different CCA cell line models with 11 different ‘epigenetic drugs (‘epi-drugs’) which target different epigenetic enzymes. By modelling the response of CCA cells to broad epi-drug concentrations , I identified GSK J4 HCl (a histone demethylase inhibitor) as the most promising drug candidate. Subsequent experiments at physiologically-attainable concentrations revealed that this while this epi-drug significantly impeded tumor cell proliferation, it did not actively induce cell death. These data indicate that the effects of epi-drug treatment are largely cytostatic and that it should be pursued as part of a combination therapy instead.
The modest survival advantage of current chemotherapy agents (<1 year) is indicative that new compounds should be evaluated as combination therapy partners for our epi-drugs. To streamline prospectively novel targeted-therapies into clinical use for CCA patients, we applied state-of-the-art high-throughput drug repositioning experiments in our previously screened cell lines. Importantly, all 465 compounds tested are already in routine clinical use or have reached the late stages of clinical trials for other diseases. Among these, I have identified a significant number of compounds with potent tumour-selective therapeutic potential, in particular heat shock protein inhibitors and chemotherapies used for other cancers.
In parallel to cell line experiments, I profiled and analysed transcriptomic, epigenomic and mutational data from over 400 CCA patients with localized disease. As expected, extensive epigenomic remodelling was identified as a hallmark of CCA which converged to dysregulate key cancer pathways. Importantly, I further obtained access to unique CCA patient autopsy samples which comprised primary tumours with matched distant metastases. Through integrative genomics, I tracked the molecular evolution of primary tumours as they spread to ultimately kill the patients and revealed that the epigenetic alterations in the primary tumour are consistently inherited by the metastases. These data suggest that metastases inherit the same epigenetic vulnerabilities as the primary tumours and therefore our candidate epigenome-directed therapies may be of benefit irrespective of the tumor stage of patients at diagnosis.
These results have been disseminated by presentations at ‘New Targets to Fight Cancer’ MSCA IF monitoring meeting (Brussels, 2017), EASL ILC (Paris, 2018), ILCA (London, 2018) and Danish Cancer Society’s ‘Metastasis as a Systemic Disease’ meeting (Copenhagen, 2017). To date, this EpiTarget fellowship has produced one first co-author research paper (PMID: 29278425) and one first co-author review paper (PMID: 28645654). Throughout my MSCA fellowship, I have generated novel datasets (epi-drug, high-throughput drug repositioning, transcriptomics, epigenomics) on CCA patients and models which will be further exploited throughout my new position as Assistant Professor in the host lab at University of Copenhagen (Feb 2019 – Jan 2023). In turn, I anticipate that this work will generate two further first author publications, one focusing on epigenomic analysis of patient tumours and the other corresponding to epigenetic agents in novel combination therapies for CCA.
