Which genes control tumour cell behaviour in the most common adult eye cancer?
- Type of funding: Early Career Investigator Award
- Grant Holder: Dr Sarah Lake
- Institute: University of Liverpool
- Region: North West
- Start date: August 2013
- End Date: October 2015
- Priority: Causes
- Eye Category:
The most common eye cancer in adults is uveal melanoma (UV). The tumour itself can cause sight loss, as can treatment such as surgery or radiotherapy. In 1 out of 2 people with uveal melanoma, the cancer spreads to the liver and this is usually fatal.
Cancer is caused by genetic changes that lead to uncontrolled growth (a tumor). Dr Lake has identified 8 genes that are changed in uveal melanoma, either in all cases or in those that are able to spread to the liver.The aim in this project is to find out which of these 8 genes are essential for the tumour to grow and spread, as these would make good “druggable” targets that could be used to develop personalised cancer treatment. Finding key genetic changes and targeting them with drugs has worked well in other types of cancer at improving quality of life and extending survival.
Functional validation of potential “druggable” targets for uveal melanoma
The most common primary intraocular tumour in adults is uveal melanoma (UM), which is usually treated with radiotherapy or surgery. The tumour itself, and such ablative therapies, can lead to significant visual impairment. Approximately 50% of all UM patients also develop metastases, which are fatal because of their resistance to chemotherapy.
Despite recent identification of GNAQ, GNA11, BAP1 and SF3B1 mutations in UM, the molecular aetiology of this tumour is not fully understood. Better understanding of the “driver” mutations in UM will allow the development of targeted therapies, as has been achieved for other cancers, including cutaneous melanoma.
Whole exome next generation sequencing of 12 UM has revealed 324 recurrent gene mutations. Hypergeometric analyses prioritised eight of these genes for further study that were either mutated in all UM or metastasising UM only, suggesting they are essential for UM development and/or dissemination.
This study aims to validate which of the mutated genes functionally regulate UM cell behaviour and how this is mediated. This will be achieved by determining the:
a) Frequency of mutations, and the expression of the corresponding protein, in a large independent cohort of UM.
b) Influence of the mutations on key aspects of UM cell behaviour (e.g. proliferation and apoptosis).
c) Molecular mechanisms underpinning mutated protein activity.
Key signalling pathways identified in this study are likely to be excellent “druggable” targets either through: a) the “re-purposing” of already available drugs; or b) the development of novel therapeutics. Thus, new personalised treatment regimens will be available to UM patients to reduce their loss of vision, and mortality.
Research updateIn this project Dr Lake and team identified one gene – CNKSR3 – that is often changed in uveal melanoma. They were able to make a lab model of what happens in the body when CNKSR3 is active in uveal melanoma cells compared to when it’s not. Results showed that the uveal melanoma cells using CNKSR3 grow faster and can move around more easily.
Dr Lake said: “The CNKSR3 gene appears to play an important role in the fatal spread of UM cells. Future studies at the Liverpool Ocular Oncology Research Group will focus on establishing exactly how CNKSR3 is controlling the behaviour of UM cells and, if this can be targeted by a drug to improve patient survival.”