Targeting p53 to suppress non-alcoholic steatohepatitis comorbid with type 2 diabetes mellitus

Liver cancer is a lethal disease with few treatment options. As a consequence of the obesity epidemic, the main causes of
liver cancer are shifting, with a decreasing proportion of new cases arising from viral infection and an increasing fraction
developing from liver disease associated with Metabolic Syndrome, a diagnosis encompassing obesity, insulin resistance,
high blood pressure, and elevated cholesterol. Within this group, patients that are also diagnosed with type 2 diabetes are
particularly susceptible to developing liver disease that progresses to cancer. Increasing our understanding of the
mechanisms propelling lethal liver disease in these patients may provide novel therapeutic avenues for an otherwise
intractable condition.
Based on preliminary findings, our research will focus on the classic tumour suppressor p53. Although typically associated
with tumour prevention, the p53 pathway has also been shown to be active in advanced liver disease. In addition, we have
found that loss of p53 dramatically accelerates liver disease progression to cancer in mouse models of liver disease
associated with Metabolic Syndrome. Building on these findings, we will interrogate the importance of the p53 pathway in
liver disease using an established mouse model of human liver disease that includes type 2 diabetes. At present, there are
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no approved treatment options for advanced liver disease. However, future work targeting p53 could reveal new
treatments by repurposing existing cancer therapies. This is something that could find use within a cohort of patients
identified in Scotland to be at-risk for developing liver cancer (The South of Scotland Monitoring Network)