Role of Bcl-2 pro-survival proteins in melanoma

Metastatic melanoma is one of the most difficult cancers to cure and recent advances in the development of targeted therapies have improved patient outcome. However, response is variable and almost all patients relapse with a cure remaining elusive. As such, there is an urgent need to identify new drug targets to treat melanoma. There is some evidence that Bcl-2 pro-survival proteins (which normally keep cells alive by inhibiting the cell death program of apoptosis) are expressed at unusually high levels in melanoma compared to normal melanocytes. Our hypothesis is that Bcl-2 pro-survival proteins provide a survival advantage for melanomas and might contribute to resistance to standard chemotherapeutic drugs.

Our research aims to identify the key Bcl-2 pro-survival proteins that are responsible for melanoma survival. This will be achieved through the use of Bcl-2 protein-selective reagents, which were engineered in the Fairlie laboratory, to profile melanoma cell lines, as well as samples from patients. The sensitivity to these reagents will be assessed in cell culture systems as well as in mouse models.

The second aim is to determine whether resistance to current melanoma treatment arises due to elevated levels of Bcl-2 pro-survival proteins, and whether treatment with Bcl-2-targeting molecules will resensitise tumours to standard drugs, informing potential drug treatment combinations. This aim will also explore whether immunotherapy approaches could benefit from Bcl-2 targeting.

Results from this project should identify potential drug targets for the treatment of metastatic melanoma.