Therapeutic targeting of Bcl-2 proteins in cancer

EF Lee1,2, MJ Herold3, L Rohrbeck3, BT Kile3, K Kroeger4, SH Gellman5, PM Watt4 and WD Fairlie1,2

  1. Olivia Newton-John Cancer Research institute
  2. La Trobe University
  3. Walter and Eliza Hall Institute of Medical Research
  4. Phylogica and Telethon Kids Institute
  5. University of Wisconsin

The cell death (apoptosis) pathway regulated by the Bcl-2 family of proteins is frequently deregulated in cancers leading to the survival of cells that should otherwise be removed. As such, there has been considerable interest in the development of new drugs that specifically target the Bcl-2 pro-survival proteins and to trigger apoptosis in tumour cells. These compounds are showing considerable promise with the first drug targeting Bcl-2 itself just gaining approval for use in patients with chronic lymphocytic leukaemia. However, not all pro-survival proteins have been targeted with these drugs, and not all cancers respond to those that have been developed. In this presentation, I will discuss our studies that have revealed which factors can influence sensitivity of cancer cells to drugs and new strategies to target Bcl-2 pro-survival proteins including our efforts to develop highly stable, cell-penetrating peptides. The effect of dual targeting of Bcl-2 proteins plus other pathways that influence cell proliferation will also be discussed.