Treatment of solid tumours by co-targeting Bcl-2 pro-survival proteins

Lee EF1, Harris T2, Tran S2, Evangelista M2, Herold MJ3 and Fairlie WD2

  1. LIMS, La Trobe University.
  2. Olivia Newton-John Cancer Research Institute.
  3. Walter and Eliza Hall Institute.

Defective apoptosis signalling is a hallmark of most, if not all, cancers. Typically this involves abnormally high expression of the pro-survival members of the Bcl-2 family of proteins. This enables damaged cell to survive when they should otherwise be removed. Over the last decade, a new class of drugs ("BH3-mimetics") has been developed to target the Bcl-2 proteins and there are now molecules that enable most of them to be selectively antagonised. In this presentation, I will discuss our recent data using a panel of these drugs on different types of highly chemoresistant solid tumours. These data combined with results from experiments using protein-based ligands we have engineered, as well as genetically engineered cell lines, have enabled us to dissect the critical "survival" factors in these tumours. Critically, we show a consistent pattern of proteins that must be antagonised to provide potent and synergistic tumour cell killing Interestingly, the same pattern is also starting to emerge for other cancers types, suggesting a potential standardised treatment strategy for many cancers using these drugs.