Targeting sphingolipid metabolism for therapeutic benefit
Targeting sphingolipid metabolism is a potential ant-cancer strategy, but the underlying mechanisms remain poorly defined. We have found that triggering accumulation of ceramide in acute myeloid leukaemia (AML) cells by inhibition of sphingosine kinase induces an apoptotic integrated stress response (ISR) through protein kinase R-mediated activation of the master transcription factor ATF4. This leads to transcription of the BH3-only protein, NOXA, and degradation of the pro-survival MCL1 protein that AML cells are highly dependent on for survival. Targeting this novel ISR pathway in combination with the BCL2 inhibitor venetoclax synergistically killed primary AML blasts, including those with venetoclax-resistant mutations, as well as leukemia-initiating cells, and reduced leukemic burden in patient-derived AML xenografts. Collectively, these findings provide mechanistic insight into the anti-cancer effects of ceramide and pre-clinical evidence for new approaches to augment BCL2 inhibition in the therapy of AML and other cancers with high MCL1 dependency.
Stuart Pitson is a NHMRC Senior Research Fellow and NRF Professor of Brain Tumour Research at the Centre for Cancer Biology, Adelaide. His research interests are in (i) examining cell signalling pathways controlled by sphingolipids, and how they contribute to cancer, fibrosis, wound healing, and other conditions, and (ii) the development of advanced patient-derived xenografts models for pre-clinical evaluation of new anti-cancer approaches. He has published over 150 papers with a number of notable contributions, including the cloning of the first human sphingosine kinase, and identification of key regulatory mechanisms regulating sphingolipid metabolism that have (patho)physiological significance, as well as the development of novel inhibitors with potential clinical application. He is also co-founder of Cincera Therapeutics and Ankere Therapeutics, two spin-out companies established through separate multi-million dollar investments.