Therapeutic targeting of HIF prolyl hydroxylases in acute myeloid leukaemia

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Studies on the blood system have in the past pioneered stem cell transplantation and delivered new therapies for cancer. Normal blood stem cells reside in the bone marrow and are responsible for life-long production of red and white blood cells. In blood cancers such as acute myeloid leukaemia (AML), normal blood stem cells are damaged and turn into cancer stem cells (CSCs) that are unable to make normal blood cells. Instead, they generate and fuel the leukaemia bulk which has devastating consequences to many tissues and organs. A major problem in cancer treatments is that the currently available therapies shrink the leukaemic bulk but they fail to eliminate CSCs, which cause the disease to return in a more aggressive form. Therefore, it is of immense importance to design new therapies that efficiently target CSCs and permanently eradicate them. In order to develop curative therapies that eliminate CSCs, it is essential to understand how these rogue cells are made and how they manage to survive currently available leukaemia treatments. The central aim of our laboratory is to understand the biology of CSCs and harness this knowledge to pharmacologically target the key biological processes in CSCs in order to therapeutically eliminate them. Recent fundamental discoveries have revealed that the bone marrow, where CSCs are generated, has remarkably low levels of oxygen (i.e. is hypoxic). Cells typically respond to hypoxia by producing molecules called 'hypoxia-inducible factors' (Hifs) that help them to adapt to low oxygen levels. We have teamed up with key international experts in hypoxia biology, Prof. Sir Peter Ratcliffe and Prof. Chris Schofield at Oxford, to understand the role of Hifs in leukaemia. We found that normal blood stem cells do not require Hifs to generate all blood cells (Guitart et al, Blood, 2013 & Vukovic et al, Blood, 2016) but, importantly, under pathological conditions, Hifs strongly protect blood stem cells from becoming CSCs (Vukovic et al, J. Exp. Med, 2015). Based on this knowledge and promising pilot studies, we now intend to conduct a pre-clinical investigation testing the hypothesis that Hifs can be used as powerful weapons to combat CSCs. Using different state-of-the-art experimental strategies in mice harbouring murine and human leukaemia we will investigate whether high levels of Hifs have the ability to kill CSCs and rescue the mice from the disease. Importantly, one of these strategies will involve testing new drugs known to pharmacologically induce high levels of Hifs and thus, if successful in mice, can be rapidly translated to the clinic. This work will provide a framework for clinical trials aiming for curative therapies in AML. We will work closely with our clinical collaborators (including Prof. Tim Somervaillle in Manchester and Dr Christoph Lutz in Heidelberg, Germany) to translate our findings for patient benefit as quickly as possible. We are in a unique position to perform this research. We have all the necessary reagents and track record and expertise in haematology and stem cell biology. Our close collaborators in Oxford are internationally recognised experts in hypoxia and cancer, and have significant interest in therapeutically manipulating Hifs in human diseases. This project will greatly benefit from such cross-discipline collaboration. Finally, MRC Centre for Regenerative Medicine has a long-term track record in pioneering discoveries in the stem cell field and this institute is an ideal place to successfully perform this study.