Uncovering and enhancing the biological activity of hypomethylating agents to treat MDS and AML.

Hosted by: Dr Rita Ferreira

Abstract

Despite the increasing reliance on hypomethylating agents (HMAs)- azacitidine (AZA) and decitabine (DAC) to treat myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), their clinical efficacy remains unpredictable and sub-optimal. To further our understanding of the relationship between in vivo drug incorporation and DNA hypomethylation in hematopoietic cells and clinical response, we conducted a phase II clinical trial, and leveraged samples to perform a comprehensive, longitudinal evaluation of bone marrow constituents in patients receiving HMAs. There were several baseline and dynamic differences between HMA responders and non-responders, which provided mechanistic insights into the biological activity of HMAs. I will present these data along with results from a genome-wide CRISPR-Cas9 screen that identified a synergy between HMAs and SUMOylation blockade, and uncovered a novel drug combination for use in AML that we are progressing towards an investigator-initiated trial.

Biography

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Professor John Pimanda is a haematologist at the Prince of Wales Hospital (POWH) and Professor of Medicine and Head, Stem Cell Laboratory at the Lowy Cancer Research Centre, UNSW Sydney, Australia. His research program is focussed on developing new strategies to improve patient outcomes in myelodysplastic neoplasms (MDS) and acute myeloid leukaemia (AML).  Other areas of specific interest include the transcriptional regulation of blood stem cell development, maintenance, and differentiation through life. He graduated in Science and Medicine at UNSW Sydney in 1994.  Following his clinical training in haematology and a PhD under the supervision of Professor Phil Hogg, he continued his research training in molecular haematopoiesis at the University of Cambridge, as the NHMRC RG Menzies/CJ Martin Fellow in the laboratories of Professors Tony Green and Bertie Gottgens (2004-2008). Following his return to Australia, he set up a research program in stem cell and leukaemia biology as a clinical academic at UNSW and POWH.  He is the principal investigator of several early phase investigator initiated clinical trials that have stemmed from research in his laboratory. He is a Fellow of the Royal Australasian College of Physicians and Royal College of Pathologists of Australasia.