Therapeutic targeting of HIF prolyl hydroxylases in acute myeloid leukaemia

过去，对血液系统的研究开创了干细胞移植的先河，并为癌症提供了新的治疗方法。正常的血液干细胞驻留在骨髓中，负责终生生产红细胞和白细胞。在急性髓系白血病(AML)等血癌中，正常的血液干细胞受到破坏，转化为无法制造正常血细胞的癌症干细胞(CSCs)。相反，它们会产生并助长白血病，这会对许多组织和器官造成毁灭性的后果。癌症治疗中的一个主要问题是，目前可用的治疗方法缩小了白血病体积，但它们未能消除CSCs，后者导致疾病以更具侵袭性的形式复发。因此，设计有效针对CSCs并永久根除它们的新疗法具有极其重要的意义。为了开发消除CSCs的根治疗法，了解这些流氓细胞是如何形成的，以及它们如何在目前可用的白血病治疗中存活下来，这是至关重要的。我们实验室的中心目标是了解CSCs的生物学，并利用这一知识在药理学上针对CSCs中的关键生物学过程，以便从治疗上消除它们。最新的基础发现表明，产生CSCs的骨髓含氧量非常低(即缺氧)。细胞通常通过产生被称为“低氧诱导因子”(HIF)的分子来应对低氧，这种分子能帮助它们适应低氧水平。我们与低氧生物学的主要国际专家，牛津大学的彼得·拉特克利夫教授和克里斯·斯科菲尔德教授合作，了解HIF在白血病中的作用。我们发现正常的血液干细胞不需要HIF来产生所有的血细胞(Guitart等人，布拉德，2013&Vukovic等人，布拉德，2016)，但重要的是，在病理条件下，HIF强烈保护血液干细胞不会成为CSCs(Vukovic等人，J.Exp。Med，2015)。基于这一知识和有前景的初步研究，我们现在打算进行一项临床前调查，以检验HIF可用作对抗CSCs的强大武器的假设。我们将在患有小鼠和人类白血病的小鼠身上使用不同的最先进的实验策略，研究高水平的HIF是否有能力杀死CSCs并将小鼠从疾病中拯救出来。重要的是，这些策略之一将涉及测试已知可在药理上诱导高水平HIF的新药，因此，如果在小鼠身上成功，可以迅速转化为临床。这项工作将为旨在治疗急性髓细胞白血病的临床试验提供一个框架。我们将与我们的临床合作者(包括曼彻斯特的Tim Somervaillle教授和德国海德堡的Christoph Lutz博士)密切合作，尽快将我们的发现转化为患者的利益。我们处于一个独特的位置来进行这项研究。我们在血液学和干细胞生物学方面拥有所有必要的试剂、记录和专业知识。我们在牛津的密切合作伙伴是国际公认的缺氧和癌症专家，他们对治疗人类疾病的HIF非常感兴趣。这个项目将从这种跨学科合作中受益匪浅。最后，MRC再生医学中心在干细胞领域的开创性发现方面有着长期的记录，该研究所是成功进行这项研究的理想场所。

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.