Developing a precision medicine approach to target leukaemic stem cells in AML.

急性髓系白血病是一种侵袭性血癌，在大多数患者中预后较差。大多数患者无法耐受提供长期缓解前景的强化化疗。尽管进行了化疗，但大多数患者会复发，一旦复发，长期存活率就会很低。因此，有一个重要的未得到满足的需要，即找出患者复发的原因，并开发更有效的治疗方法来防止复发。我们现在知道，白血病干细胞是抵抗化疗并最终复发的根本原因。这些相对罕见的细胞在确诊时存在，与大多数白血病细胞非常不同。目前的任何治疗方法都不能有效地针对它们。蛋白质是我们细胞的基石，并最终决定细胞的行为。之前的许多研究都对白血病的基因变化进行了详细的研究，但对于这种变化如何影响蛋白质的变化，人们确实缺乏了解。最近的研究表明，白血病干细胞和其他白血病细胞之间有很多不同之处，只能通过蛋白质而不是基因来观察，可能是识别和靶向这些细胞的关键。这个项目计划在蛋白质水平上识别这些关键细胞的特殊脆弱性，并利用这些差异来开发真正有针对性的、毒性较低的疗法。该战略是开发保护健康正常血液干细胞的治疗方法，与目前的治疗方法形成对比，降低严重感染的风险和化疗的毒副作用。这种方法有可能改变急性髓细胞白血病的治疗方法，为尽管存在其他健康问题而安全有效地治疗老年人提供机会，减少人们在医院停留的时间，并转向提高生活质量和长期生存的家庭治疗。

Acute myeloid leukemia is an aggressive blood cancer with poor outcomes in the majority of patients. The majority of patients are unable to tolerate the intensive chemotherapies offering the prospect of prolonged remissions. Despite chemotherapy, the majority of patients will relapse, and long-term survival is poor once this has occurred. There is therefore an important unmet need to work out why patients relapse, and develop more effective therapies to prevent relapse.We now know that leukaemic stem cells are the underlying reason for resistance to chemotherapy and ultimately relapse. These relatively rare cells are present at diagnosis, and are very different from the majority of leukemia cells. They are not targeted effectively by any current treatments. Proteins are the building blocks of our cells, and are ultimately responsible for how cells behave. Many previous studies have looked in detail at genetic changes in leukemia, but there is a real lack of understanding of how this affects changes to proteins. Recent work has shown that there are lots of differences between leukemia stem cells and other leukaemia cells, which are only seen by looking at proteins rather than genes, and may hold the key to identifying and targeting these cellsThis project plans to identify the particular vulnerabilities of these key cells at a protein level, and use these differences to develop truly targeted and less toxic therapies. The strategy is to develop therapies which protect healthy normal blood stem cells, in contrast to current treatments, reducing the risk of severe infections and the toxic side effects of chemotherapy. This approach has the potential to create a step-change in treatment of AML, opening up opportunities for treating older people safely and effectively despite other health problems, reducing the time people spend in hospital and moving towards home-based treatments which improve both quality of life and long-term survival.