Therapeutic targeting of HIF prolyl hydroxylases in acute myeloid leukaemia

过去对血液系统的研究是干细胞移植的先驱，并为癌症提供了新的治疗方法。正常的血液干细胞存在于骨髓中，负责红细胞和白细胞的终身生产。在像急性髓性白血病（AML）这样的血癌中，正常的血液干细胞被破坏，变成不能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，对许多组织和器官造成毁灭性的后果。癌症治疗的一个主要问题是，目前可用的治疗方法缩小了白血病的体积，但它们不能消除csc，这导致疾病以更具侵略性的形式复发。因此，设计有效靶向CSCs并永久根除它们的新疗法是非常重要的。为了开发消除CSCs的治疗方法，了解这些流氓细胞是如何产生的，以及它们是如何在目前可用的白血病治疗中存活下来的，是至关重要的。我们实验室的中心目标是了解CSCs的生物学特性，并利用这些知识从药理学上靶向CSCs的关键生物学过程，以便在治疗上消除它们。最近的基础发现表明，骨髓（造血干细胞产生的地方）的氧含量非常低（即缺氧）。细胞对缺氧的典型反应是产生一种叫做“缺氧诱导因子”（hif）的分子，帮助细胞适应低氧水平。我们与牛津大学的Peter Ratcliffe教授和Chris Schofield教授等缺氧生物学领域的主要国际专家合作，以了解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来生成所有的血细胞（Guitart等人，blood， 2013 & Vukovic等人，blood, 2016），但重要的是，在病理条件下，hif强烈保护血液干细胞不成为csc （Vukovic等人，J. Exp. Med, 2015）。基于这些知识和有希望的试点研究，我们现在打算进行临床前调查，测试hif可以作为对抗csc的有力武器的假设。使用不同的最先进的实验策略，在小鼠和人类白血病中，我们将研究高水平的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，其中一种策略将涉及测试已知能在药理学上诱导高水平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AML治疗性治疗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 somervaille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。我们在进行这项研究方面处于独特的地位。我们在血液学和干细胞生物学方面拥有所有必要的试剂、跟踪记录和专业知识。我们在牛津大学的密切合作伙伴是国际公认的缺氧和癌症专家，并对人类疾病的治疗性操纵hif有很大的兴趣。这个项目将从这样的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，该研究所是成功开展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.