[WS4] APPA/PSSJ Joint Workshop Toward International Cooperation in Protein Science

[WS4-10] Targeting the BCL-2-regulated cell death pathway for the treatment of cancer

Fairlie WD^1,2,3, Arulananda S¹, O’Brien M¹, Harris TJ¹, Tran S^1,2, Steinohrt NS¹, Evangelista M¹, Jenkins LJ^1,2, Poh AR¹, Rohrbeck L⁴, Thapa B¹, Williams DS¹, Cebon J¹, Behren A¹, Herold MJ⁴, Haass NK⁵, Mariadason JM¹, John T⁶, ^○Lee EF^1,2,3 (1.Olivia Newton-John Cancer Research Institute, 2.School of Cancer Medicine, La Trobe University, 3.Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, 4.Walter and Eliza Hall Institute, 5.University of Queensland Diamantina Institute, 6.Peter MacCallum Cancer Centre)

Many cancers remain resistant to currently available treatments, hence, require urgent research. The unwarranted survival of cancer cells is often due to their ability to escape self-destruction by apoptotic cell death regulated by the BCL-2 protein family. Anti-cancer therapeutics known as “BH3-mimetics” influence cancer cell survival by antagonising the pro-survival members of the BCL-2 family. One such drug, Venetoclax, is now used in the clinic for the treatment of some blood cancers, whilst others are in clinical trials or pre-clinical testing.
Our research focusses on the application of BH3-mimetics for the treatment of cancers. We have developed a comprehensive experimental pipeline, involving chemical parsing with clinically relevant BH3-mimetics, gene editing, and interrogation of standard-of-care chemotherapy combinations in cell lines, patient-derived tissues and animal models. To date, we have identified therapeutic targets and novel chemotherapeutic combinations in a range of aggressive solid cancers with low survival rates (<1 year), including melanoma, mesothelioma and biliary tract cancers.
Our data provides a compelling rationale for the clinical investigation of targeting the BCL-2-regulated cell death pathway for the treatment of a range of solid cancers. Targeting generic pathways essential to the survival of tumours is an attractive approach benefitting cancers lacking well-characterised genetic defects.