Miss Emma Morrish - Inflammation division

Miss Emma Morrish - Inflammation division

Davis Auditorium
Start Time: 
Wed, 11/09/2019 - 1:00pm
End Time: 
Wed, 11/09/2019 - 2:00pm

Targeting MDR1 potentiates IAP inhibitors to overcome treatment resistance in AML

Wednesday seminar (this is a PhD Completion seminar)​ hosted by Dr Gabriela Brumatti

Overexpression of inhibitor of apoptosis (IAP) proteins, responsible for the regulation of TNF-mediated apoptosis, have been correlated with cancer progression and treatment resistance. Natural IAP antagonists exist, leading to the pharmaceutical development of Smac-mimetics (SMs). The clinical SM birinapant is currently in clinical trials for a range of cancers, including acute myeloid leukaemia (AML). AML is an aggressive disease with a current 5-year survival rate of only ~30%. Although, birinapant has shown promising anti-cancer effects, boosting its efficacy and overcoming resistance are still major challenges.

During her PhD, Emma has examined the emergence of resistance to birinapant in AML and has identified multidrug resistance protein 1 (MDR1/ABCB1) inhibitors as a class of clinical drugs that can overcome SM resistance in cancer. Emma and colleagues have shown that inhibiting MDR1 in SM resistant leukaemia cells leads to an increase in the intracellular levels of birinapant, ultimately sensitising AML cells to birinapant killing. Furthermore, analysis of different AML models and patient samples revealed that expression/activity of MDR1 is a predictor of response to birinapant-based therapies in cancer cells. Emma and colleagues have illustrated that co-inhibition of MDR1 and IAPs is well-tolerated in vivo and more effective against leukaemic cells, compared to normal haematopoietic progenitors. Importantly, they have shown that birinapant combined with MDR1 inhibitors effectively kills leukaemia stem cells (LSCs) and prolongs survival in vivo. Altogether, Emma’s research has helped identify MDR1 as a biomarker of SM treatment and revealed a new combination therapy that can potentiate SM treatment, suggesting a therapeutic opportunity for AML patients.