Precision medicine in cholangiocarcinoma: accurate tools for early detection and identification of PRMT5 as a novel pharmacological target
Background: Cholangiocarcinoma (CCA) patients´ survival 5 years post diagnosis is <10%. This is mainly due to late diagnosis and few effective drugs, including some targeted agents. Better tools for early accurate diagnosis and effective therapies are needed.
Hypothesis: 1. NGS-based mutagenic analysis of bile cell free DNA (cfDNA) has very high sensitivity for early CCA diagnosis, far superior to current procedures. Thus, bile may be a liquid biopsy matrix to detect CCA. 2. CCA treatment can be improved by targeting epigenetic pathways.
Aims: 1. Demonstration of bile as a liquid biopsy matrix for CCA diagnosis. Primary: Prospective validation of bile cfDNA NGS analysis as a diagnostic tool in patients with suspicion of CCA. Secondary: Characterize the bile bacterial microbiome and bile acid (BA) profile in CCA patients. 2. Identification of protein arginine methyltransferase 5 (PRMT5) as a novel target in CCA. Primary: Validate PRMT5 overexpression in CCAs and the antitumoral effects of its inhibition. Secondary: Identify PRMT5’s mechanisms in CCA development and drug resistance.
Methods: Aim 1. We will collect bile from patients with newly diagnosed undetermined biliary stenoses and test bile cfDNA with a commercial NGS panel. Diagnostic sensitivity and specificity will be compared with current clinical tools. We will analyze bile microbiome and BA profile, establishing clinical correlations. Aim 2. We will confirm PRMT5 expression in large cohorts of CCA tissues. Clinical correlations will be established. We will test antitumoral effects of PRMT5 inhibition in CCA cells, organoids and relevant mouse models. Molecular mechanisms will be studied.
Expected results and impact: Bile cfDNA NGS analysis will revolutionize CCA diagnostic speed and accuracy. Candidates for targeted therapy will be identified. Analysis of bile microbiome and BAs will provide pathogenic insights. PRMT5 validation as therapeutic target will accelerate the performance of clinical trials.
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This project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No. 964264.