Overexpression of the pro-survival members of the BCL-2 family of proteins, giving rise to deregulated apoptotic cell death, is a hallmark of most cancers. A new class of anti-cancer therapeutics known as “BH3-mimetics” influence cancer cell survival by binding and antagonising the function of the pro-survival BCL-2 proteins. One such drug, Venetoclax, was recently granted accelerated approval by the FDA as a breakthrough therapy for the treatment of chronic lymphocytic leukaemia.

In humans, there are five pro-survival proteins (BCL-2, BCL-XL, BCL-W, MCL-1 and BFL-1), of which all but BFL-1 have been targeted with small molecule BH3-mimetics. As BFL-1 has been implicated as a survival factor for cancers such as melanoma and haematological malignancies, it is a potential therapeutic target for the treatment of these diseases. We have engineered a BFL-1-selective peptide-based ligand using phage display technology. Using an array of biochemical methods, cell viability assays and mouse tumour xenograft models, we provide strong proof-of-principle for the development of a BFL-1-targeting drug.

In addition to deregulated apoptotic cell death, unwanted proliferation caused by aberrant MYC expression is another hallmark of cancer. Interestingly very few studies have examined the effect of combining direct antagonists of MYC and BCL-2 proteins for the treatment of cancer. A possible reason for this is the lack of direct MYC inhibitors as this oncogene is frequently referred to as being undruggable due to its structure. Instead, compounds that indirectly affect MYC transcription (e.g. JQ1) have been developed and shown to induce tumour cell death.

Here, we have examined the effects of co-delivering BH3-mimetics, together with novel peptide-based direct MYC inhibitors. In preliminary studies, we have shown that such combinations provide significant synergy in haematological cancers and provide exciting proof-of-principle for the treatment of cancer by co-targeting critical cell survival pathways.