Can we stop cancer spreading from the eye to the liver?
Research details
- Type of funding: PhD Studentship
- Grant Holder: Prof Sarah Coupland
- Institute: University of Liverpool
- Region: North West
- Start date: October 2014
- End Date: September 2018
- Priority: Causes
- Eye Category: Ocular cancer
Overview
In about half of patients with a rare eye cancer known as uveal melanoma, the cancer eventually spreads to the liver. If so, it is usually fatal. Surgery and radiotherapy work well to treat the tumour in the eye but so far nothing improves survival once uveal melanoma cells have spread.
The research team thinks a gene called BAP1 could be involved in whether the cancer spreads. Treating uveal melanoma cells in a lab dish with a group of drugs called ‘histone deacetylase inhibitors’ makes them less aggressive. And research has shown that BAP1 is ‘switched-off’ in up to about 8 in 10 uveal melanomas that spread.
So in this project the team is using samples from patients to find out more about how BAP1 and histone deacetylase inhibitors work and interact. They want to know what changes happen inside the cell that mean the cancer can start spreading. They also want to find out how well different histone deacetylase inhibitors do at making the cancer cells less able to spread.
If the team can show that histone deacetylase inhibitors can stop or slow the aggressive behaviour of uveal melanoma cells, it would pave the way towards clinical trials of one or more of these drugs. Data from the study will also be used to follow up patients after several years to find out whether measuring BAP1 activity could help to predict an individual’s risk of having cancer spread from the eye to the liver. If so, this could become a routine part of NHS testing.
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Scientific summary
Novel isogenic models of BAP1-deficient uveal melanoma for drug discovery
Half of uveal melanoma (UM) patients develop untreatable metastatic disease. Metastasizing UM frequently display loss of function of the deubiquitylase BAP1. One potentially interesting class of drugs for metastatic UM therapy are histone deacetylase inhibitors (HDACi) that in vitro result in a less aggressive UM phenotype. Our data demonstrate that BAP1 depletion alters HDAC protein expression in lung cancer and decreases cellular HDAC enzyme activity, thereby increasing HDACi cytotoxicity. Further, the team’s data shows UM have variable low expression of HDAC2, whilst HDAC1 is more highly and uniformly expressed. Assessing the broader HDAC family expression profile in UM, and establishing their relationship with BAP1, is key to selecting specific HDACi that will be most effective for anti-tumour 13. None of the above 3 therapies. Currently we also lack robust in vitro models for drug sensitivity screening in BAP1 null UM.
The team aims to improve our understanding of the mechanisms and consequences of BAP1 loss of function in UM, and to demonstrate how this can be exploited to develop therapeutic regimens, which may be directly assessed in clinical trials. Specifically they are: (1) Determining the mechanism for BAP1 loss of function in UM by assessing the mutation status, epigenetic regulation and protein expression in a well-characterized cohort of UM samples. (2) Determining which HDACs are expressed in UM and how these correlate with BAP1 status. (3) Generating a BAP1 ‘null’ isogenic UM cell line using rAAV-mediated gene editing. (4) Evaluating efficacy of broad-spectrum and class-specific HDACi in reducing viability, metastatic potential, or differentiation of UM in this model.