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Mechanisms underlying hepatocellular carcinoma pathogenesis and impact of co-morbidities.

Periodic Reporting for period 1 - HEP-CAR (Mechanisms underlying hepatocellular carcinoma pathogenesis and impact of co-morbidities.)

Reporting period: 2016-01-01 to 2017-06-30

Hepatocellular carcinoma (HCC) is the second most common cause for cancer related death in the world, with an estimated 750,000 new cases and 695,000 deaths per year. WHO estimate that HCC is responsible for around 47,000 deaths per year in Europe. HCC develops from chronic and progressive liver injury that arises via an array of insults to the liver including obesity associated non-steatohepatitis (NASH); alcohol-related steatohepatitis (ASH), chronic hepatitis B and C virus (HBV/HCV) infection. These co-morbidities impact on both diagnosis and treatment response, however, they are not currently considered in patient management guidelines. Recent health economic studies in Europe have estimated the incidence and mortality rates of HCC of 65,000 and 60,240 cases. In almost all populations, males have higher liver cancer rates than females, with male:female ratios usually averaging between 2:1 and 4:1. Given prevailing demographic and life expectancy trends, the number of HCC patients is expected to be as many as 78,000 in 2020. Studies indicate that the number of HCC related hospitalizations are increasing compared with two decades ago, causing significant direct costs. Thus, HCC is a cause of a significant and increasing overall burden for health systems and society overall and the increasing number of individuals with HCC may have major public health and economic implications.
Given the limited efficacy of current treatments and the huge social implications of HCC progression, this highlights the urgent need to define common and co-morbidity specific pathways and associated bio-markers for patient stratification to improve diagnosis and therapy. The past decade has generated solid information about the molecular, viral and immune mechanisms that contribute to HCC disease progression, however, this knowledge has not transferred into clinical practice. Importantly, there is a lack of pre-clinical HCC models to validate therapeutic targets and to support new drug discovery programmes.
The HEP-CAR consortium will extend and integrate the pathophysiological knowledge on HCC to determine the impact of co-morbidities on the prevention and treatment of HCC. Our goal is to develop and validate informed management strategies based on the major co-morbidities associated with HCC progression in the European population. HEP-CAR will employ the multidisciplinary skills of selected European partners with expertise in liver disease and who have well characterised HCC cohorts and excellent resources to address the objectives of the project.
Knowledge obtained in HEP-CAR will be instrumental in the future management of HCC patients, specifically for individualized diagnosis and treatment of HCC and associated co-morbidities.
The work performed in the first 18 months and the results achieved so far are detailed below:
Genomic and transcriptomic analyses of large HCC sample collections were performed to identify drivers of HCC development with respect to co-morbidities. In parallel we investigated mouse model systems recapitulating distinct HCC tumour characteristics and started to determine the impact of co-morbidities on HCC development and progression. In this regard we identified first candidate markers like STAT3, PTPRD or ATX which might be valuable tools for improving tumour progression prognosis as well as possible targets for intervention. In addition we made significant progress in understanding how immune pathways contribute to prevention of HCC formation and might also be used to develop highly effective therapy approaches. We identified a large number of phosphopeptides to be promising novel tumour-associated antigens (TAAs). Lack of specific TAAs is the current bottleneck in analysis of HCC-specific immune responses. With these novel TAAs we started to investigate the presence of tumour-specific immune responses in detail to determine potential manipulation strategies to improve immune responses contributing to curative treatments of HCC.
HEP-CAR will move beyond current state of the art by defining the molecular pathways associated with HCC co-morbidities, specifically NASH, chronic HBV and HCV infection and thus allowing us to personalize health policy and advice. HEP-CAR will identify biomarkers that have innovation potential, possibly leading to the development of novel screening tools to allow individuals and clinicians to focus on lifestyle (e.g. NASH) or specific therapeutic interventions (e.g. HBV, HCV) to prevent disease progression.
The first three years of the action will define the relative contribution of different molecular, viral and immune pathways and causes (“help modifiers”) of HCC by studying these in relevant human populations and experimental models. This will allow the integration of existing knowledge about the molecular mechanisms of HCC and the relative contribution of co-morbidities with clinical presentation and assessment of patients. A specific set of markers will be identified that can be used in the clinical setting to define the relative risk of patients for HCC development, progression and treatment with respect to their existing co-morbidity. In the final part of the project, the identified pathways will be validated and transferred to independent well-characterized patient cohorts assembled by partners of the Consortium.
In summary, the identification co-morbidity specific or common drivers that associate with HCC progression or diagnosis will provide algorithms to plan and evaluate stratified interventions to prevent and manage HCC in the future. Such advances have the potential to impact on morbidity, mortality and costs to the European population caused by HCC.
Management structure of HEP-CAR project
Graphical presentation of the project Workpackages showing how they inter-relate
HEP-CAR Consortium