Mark A. Guthridge

Mark A. Guthridge

Monash University, Australia

Title: The selective targeting of cell survival pathways in acute myeloid leukemia


Dr. Mark Guthridge completed his Ph.D studies at Monash University after which he took up a postdoctoral position at New York University Medical Centre as a Darland Research Fellow. He returned to the Institute of Medical and Veterinary Science, Adelaide Australia in 1998 and was awarded a Peter Nelson Leukemia Research Fellowship to examine molecular approaches for the therapeutic targeting of acute myeloid leukemic (AML) cells. In 2011 Dr. Guthridge moved his laboratory to the Division of Blood Cancers at the Australian Centre for Blood Diseases (ACBD) located on the Alfred Medical Research and Education Precinct (AMREP) in Melbourne. Since 2000, Dr. Guthridge's lab has received continual funding from International (NIH, AICR), National (NH&MRC, LFA) and State agencies (Cancer Council of SA). His work has been published in top-tier journals including Cell, Molecular Cell, Cell Stem Cell and EMBO J as well as leading specialist cancer/hemopoietic journals such as Blood, Leukemia and Cancer Research. Dr. Guthridge regularly serves of NH&MRC GRPs and is co-convenor of the New Directions in Leukaemia Research (NDLR) conference held biennially on the Sunshine Coast, QLD. Dr. Guthridge’s research focuses on the mechanisms by which cancer cells co-opt and coerce intracellular signalling pathways to promote deregulated cell survival, proliferation and growth. Through the molecular analysis of intracellular signalling pathways, Dr. Guthridge’s laboratory seeks to identify new therapeutic targets in diseases such as leukaemia



Oncogenic activation of cell survival programs is a classical hallmark of cancer, allowing malignant cells to evade cytotoxic therapies. Although the concept of targeting cell survival in cancer has long been proposed, it has not yet proven clinically successful for the majority of cancers including acute myeloid leukemia (AML). We have identifi ed a novel tyrosine kinase independent signalling mechanism by which diverse growth factor receptors regulate cell survival but not other cellular responses such as proliferation. We show that this “survival only” response is regulated via non‐canonical growth factor receptor pathways that, remarkably, require the protein kinase activity of phosphoinositol 3‐kinase (PI3K) but not its lipid kinase activity. Th e protein kinase activity of PI3K is constitutively activated in >80% of primary human AML patient samples and selective targeting of this novel PI3K pathway either pharmacologically or by RNAi results in the rapid induction of apoptosis. We therefore screened compound libraries for drugs that target “survival‐only” pathways and have identifi ed the kinase inhibitor, PIK‐75, that is a potent inducer of apoptosis across a panel of 44 genetically diverse primary AML cases (mean IC50=395nM) at concentrations which did not aff ect the viability of non‐transformed human bone marrow progenitors (p=0.0074). PIK‐75 represents a fi rstin‐ class compound that blocks survival signalling in AML cells through dual inhibition of PI3K and the transcriptional kinase, cyclin dependent kinase 9 (Cdk9)(Kd<10nM), thereby transiently blocking RNA Polymerase II‐mediated transcription leading to the rapid loss of the prosurvival protein, Mcl‐1. Our studies reveal a previously unrecognized alliance between PI3K and Cdk9 in promoting oncogenic survival signals and we show that the simultaneous inhibition of PI3K and Cdk9 is highly synergistic not only AML cells (combination index <0.2), but tumor cells derived from multiple myeloma, breast cancer and brain cancer. Importantly, PIK‐75 treatment is well tolerated in mice, results in the signifi cant reduction of leukemic loads in mice engraft ed with human AML cells (p=0.0059), and signifi cantly increases their median survival (p=0005). Th us, our studies identify a novel lead compound that selectively targets two distinct and independent regulators of survival in AML. With the limited clinical effi cacy reported so far for many kinase inhibitors, further investigation of dual PI3K and Cdk9 inhibitors is warranted.

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