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Transcribed-Ultraconserved Regions as novel biomarkers and therapeutic targets in liver cancer

Final Report Summary - LIVERNCODE (Transcribed-Ultraconserved Regions as novel biomarkers and therapeutic targets in liver cancer)

This award funded my research exploring the role of non coding RNAs (ncRNA) in primary liver cancers. Using a combination of animal models, in vitro technologies and human samples, we have identified specific ncRNAs that are downstream of the Wnt pathway and determine deregulation of microRNA expression. We showed that this ncRNA not only is a downstream effector of the Wnt pathway but is also specific for cancer development. These studies are of great importance in light of the current effort to investigate Wnt inhibitors in liver cancers, and will inform the design of clinical trials based on ncRNA-mediated patients’ selection.
In order to explain the specificity of this ncRNA overexpression to the cancer process we have hypothesized that this may be related to the stroma and the activation of a specific immune response that is lacking in absence of malignant transformation. Thus, we have transcriptionally characterized the the tumour and peri-tumour areas of human resected primary liver cancers, and identified a transcriptional deregulation in the peritumoural stroma that reflects into clinical outcome. We have proposed selected candidate transcripts that may be used as biomarkers in resected cancers given their correlation with the risk of relapse and the benefit from adjuvant chemotherapy. These data will launch validation in larger datasets that may potentially lead to changes in clinical practice. In parallel we have promoted a program of biomarker discovery for small molecule drugs, and we have tested a panel of hepato-biliary cell lines against a library of 500 small molecule targeted drugs and associated the response to their cellular mutational profile and microRNA expression. We were able to describe a microRNA mediated mechanism of resistant to HSP90 inhibitors by using a combination of in vitro knock-out cell lines, inducible clones, in vitro 3D models and patients derived xenografts. In addition, we have reported the first success in establishing human Patients’ Derived Organoids from a single core of image-guided biopsies in primary liver cancers.
Last, we have transferred this knowledge in liver cancers into other forms of solid tumours, such as pancreatic cancers, and have provided evidence for the prognostic and predictive value of non coding RNAs in this disease.

The Marie Curie Career Integration grant has facilitated my integration within the research community of the European Union and has enabled my networking with international research groups for the implementation of a plan of actions that aims at advancing the understanding of primary liver cancers and their clinical management.
On a personal perspective the award has facilitated my academic career providing funding that supported my research, allowed securing of additional grants and enabled the establishment of my independence as a Clinician Scientist.