Integrative analysis of BAP1 dependencies to identify novel therapeutic targets for uveal melanoma: learning lessons from the lung

Integrative analysis of BAP1 dependencies to identify novel therapeutic targets for uveal melanoma: learning lessons from the lung

Brief Lay Background

Uveal melanoma (UM) is a rare but aggressive tumour of the eye. Treatment of UM before it has spread is usually successful, but vision cannot always be saved. Once UM has spread there are few available treatment options.

There are usually only a handful of genetic mutations that cause UM. One of the most common mutations is loss of a gene called BAP1.

People who inherit a non-functional BAP1 gene tend to be at risk of multiple cancers including UM and a tumour of the lung called malignant pleural mesothelioma.

What problem/knowledge gap does it help address

The BAP1 gene is essential for cell survival, which means it is difficult to create laboratory models of cells lacking BAP1, because they cannot survive. This has been a barrier to research into treatments targeting BAP1, to date.

However, this vulnerability also means that UM cells that have lost BAP1 must undergo some type of reprogramming to survive. Stopping this reprogramming could kill UM cells and is a promising treatment strategy.

Despite the challenges of growing cells lacking BAP1, Professor Coulson’s lab has engineered lung cancer cells to have just enough BAP1 to ensure survival, but a low enough amount to mimic loss of the gene. Using these cells, her team has identified the reprogrammed processes lung cancer cells use to compensate for a lack of BAP1.

Aim of the research project

To build on what is known about BAP1 in lung cancer to identify new vulnerabilities in UM cells that can be targeted by potential treatments and start to assess the effectiveness of these treatments.

This award will also contribute to building capacity in research as it will lead to a PhD for an early career researcher.

Key procedures/objectives

1. Test whether the processes reprogrammed in lung cells are also reprogrammed in UM cells that lack BAP1.
2. Carry out experiments to confirm that these processes are linked to the absence or presence of BAP1 in UM and are consistently reprogrammed when BAP1 is lacking. This is an essential step in validating the importance of a potential drug target.
3. Test potential drugs that target the processes identified in the first part of the project, to see whether they have anti-tumour activity in models of UM.

Potential impact on people with sight loss

If successful, this project could identify potential treatments ready for testing in patients with UM in a clinical trial.