Associate Professor John Silke, Cell Signalling and Cell Death Division, The Walter and Eliza Hall Insitute of Medical Research, Melbourne, VIC.
Resistance to chemotherapy is a major problem in cancer treatment and frequently associated with failure of tumor cells to undergo apoptosis. Birinapant, a Smac-mimetic, has been designed to mimic the interaction between Inhibitor of APoptosis proteins (IAPs) and Smac/DIABLO, thereby relieving IAP mediated caspase inhibition and promoting apoptosis of cancer cells. In some cancers however Smac-mimetics have a two-fold action by promoting the inflammatory cytokine TNF and sensitizing cells to the cytotoxic activity of TNF. I will discuss two exciting new studies investigating mechanistically how SMs kill Acute Myeloid leukemias and showing that killing can be increased in vitro and in vivo using two very different and completely unexpected classes of clinical compounds, anti - inflammatory p38 inhibitors and caspase inhibitors. A therapeutic breakthrough in AML has eluded the clinic for decades. Demonstrated anti-leukemic efficacy and tolerance to our novel combinations in vivo suggests two exciting new therapeutic opportunities in AML.