Targeting oncogene induced anti-apoptotic pathways for precision prevention in liver cancer

Background: Liver cancer, of which hepatocellular carcinoma (HCC) is the most common, is a global healthcare problem of unmet need. Its ever-growing disease burden mirrors the rising incidence of conditions that drive it.

These coupled with current insufficient early detection plus ineffective and financially-challenging therapy options means that prevention has to become central to tackling this disease. Using human-relevant HCC disease models we can model the premalignant stages.

Here clones with sufficient mutations to form end-stage disease may continue into late disease, get stuck in a premalignant state or be removed entirely. Preliminary data from these models show that we can identify and utilise forms of therapy (e.g. BH3-mimetics, which induce apoptosis) for cancer prevention, as they are specifically active in early disease.

However, we also see that altering the liver’s metabolic environment, through modelling obesity and NAFLD (non-alcoholic fatty liver disease, which is now the major underlying condition causing HCC), alters both the immune environment (which clears premalignant clones) and the efficacy of preventative therapy (BH3-mimetics).

We will explore premalignant clones in the presence of NAFLD, to understand how they adapt within this metabolic and immune dysregulated environment to identify targets for precision prevention in HCC.

Aims: We aim to understand the compensatory mechanisms that premalignant clones employ to avoid clearance in the steatotic liver to progress to cancer so that we can target these for preventative therapy translation to patients at risk of HCC development.

Methods: We will use preclinical models based on the human HCC, validated against late-stage HCCs, as single cells grow into late-stage tumours.

We will characterise the mechanistic adaptations as a premalignant clone establishes cancer over time within this steatotic microenvironment.

We will compare these adaptations across a range of HCC subtypes and exploit the adaptive mechanisms these cells undergo for therapies to promote their destruction.

This will include targeting compensatory anti-apoptotic pathways and mechanisms of avoiding immunogenic cell death (ICD) and immune recognition.

How the results will be used: Results from these preclinical studies will be used as a steppingstone to validate the model systems we use against early-stage human disease and to develop a proof-of-principle for precision prevention in HCC.

We will develop an early-stage organoid platform which can be used for high throughput (HTP) screening for target identification and aim to take our preclinical studies forward to integrate with patient cohorts for testing efficacy of preventative therapies in the future.