Targeting the BCL-2-regulated apoptotic pathway for the treatment of melanoma

Apoptosis is a genetically programmed form of cell death required for the removal of damaged, redundant or dangerous cells. Resistance to apoptosis is a hallmark of cancer and a critical feature of tumour development and therapeutic resistance. Genetic defects such as gene amplifications that lead to over-expresssion of the pro-survival members of the BCL-2 family of proteins (BCL-2, BCL-XL, BCL-W, MCL-1 and BFL-1) often give rise to cancer.

A new class of drugs, BH3-mimetics, has been developed to trigger apoptosis in cancer cells by targeting the critical survival factors within the tumour. Such compounds have shown promise in clinical trials for the treatment of hematological malignancies in which BCL-2 pro-survival proteins play a well-defined oncogenic role. However, currently available BH3-mimetics only target three of the five members (BCL-2, BCL-XL, BCL-W) of the BCL-2 pro-survival protein family. Hence cancers reliant on MCL-1 or BFL-1 are resistant to these BH3-mimetics.

Our preliminary work suggests that BFL-1 is critical to enabling the survival of melanoma. Further validation of the role of this pro-survival protein in a more relevant clinical setting is underway to provide proof-of-principle of the development of drugs that target BFL-1. Based on the data demonstrating a role for BFL-1 in melanoma survival, we are undertaking three parallel approaches to develop small molecule drugs against BFL-1. Success with this project will validate a new therapeutic target for the treatment of melanoma and potentially result in the development of novel drugs for the treatment of melanoma which is currently an incurable disease.