Cross-Faculty Seminar Series: Targeting cell survival and proliferation pathways in cancer

Targeting cell survival and proliferation pathways in cancer
Erinna Lee (La Trobe University)
Abstract: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.
 
Bio:Erinna is interested in understanding the molecular mechanisms underlying cell fate decisions dictated by the processes of apoptosis, proliferation and autophagy. She employs biochemical, cell biology and structural approaches, as well as mouse models, to research how these pathways give rise to cancer when deregulated and how they can be targeted therapeutically. Erinna was awarded her PhD from The University of Melbourne in 2007, under the supervision of Prof. Peter Colman and Dr. Douglas Fairlie. From 2007-2015, she was a postdoctoral fellow in the Structural Biology Division at The Walter and Eliza Hall Institute of Medical Research. In January 2016, she was awarded an ARC Future Fellowship and appointed a laboratory head within the Department of Chemistry and Physics at La Trobe University and is based as a visiting scientist at the Olivia Newton-John Cancer Research Institute.
 
Date & Time: Wednesday 19 April at 4.00 pm followed by Happy Hour.