LIVERNCODE · Transcribed-Ultraconserved Regions as novel biomarkers and therapeutic targets in liver cancer
FP7 — People (Marie Curie Actions)
- Duration
- 2013-10-01 → 2017-09-30
- EU contribution
- €100,000
- Participants
- 2
- Scheme
- MC-CIG
Lines connect the coordinator with its partners.
Results in brief
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. http://www.icr.ac.uk/our-research/researchers-and-teams/dr-chiara-braconi
Data: CORDIS, © European Union
Project objective
Hepatocellular carcinoma (HCC) is the sixth most common malignancy in the world. In Scotland incidence of liver cancer has increased of 60% in men from 2000 to 2010. The outcome of patients with advanced HCC remains poor. Thus, novel therapeutic approaches based on targeting oncogenic driver pathways in HCC are urgently needed, as well as informative prognostic markers that guide the use of existing and novel therapeutic strategies. Non-coding-RNAs (ncRNA) are implicated in liver carcinogenesis. Sequence conservation across species has been postulated to indicate that a given ncRNA may have a cellular function. A genome-wide survey identified 481 genomic sequences that showed 100% identity across the human, mouse and rat genomes. These ultra-conserved regions (UCR) are transcribed as ultraconserved ncRNAs (T-UCR). As they are so finely conserved we hypothesize they may have an essential role in regulating cell homeostasis and that may give rise to cancer when are aberrantly modified. In these studies we will profile the expression of T-UCR in human HCC tissues and in mouse HCC models that have genetic abnormalities similar to those found in human HCC to select the best candidate T-UCRs with a role in HCC pathogenesis and progression. In vitro analyses will be performed to characterize the transcript of T-UCR and assess the mechanism of action. We will evaluate the prognostic value of selected T-UCR by retrospectively and prospectively assessing their expression in a series of human HCC from patients who underwent radical resection or liver transplantation, in order to assess whether their expression may predict tumour recurrence. As we have in vitro data on the efficacy of anti-T-UCR, we propose to study if therapies based on the silencing of T-UCR may prevent tumour formation in animal model. These studies will provide evidence for the use of T-UCR as biomarkers and therapeutic targets in HCC.
Original text from CORDIS.
Participants
- INSTITUTE OF CANCER RESEARCH: THE ROYAL CANCER HOSPITAL LBG · LondonCoordinatorUnited Kingdom
- UNIVERSITY OF GLASGOW · GlasgowUnited Kingdom
Links
Data: CORDIS, © European Union