Targeting the evolving proteome in healthy and malignant stem cell development.

针对健康和恶性干细胞发育中不断进化的蛋白质组。

• 批准号: MR/X007146/1
• 负责人: William Grey
• 金额: $ 176.37万
• 依托单位: University of York
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX007146%2F1
• 关键词: Targeting; evolving; proteome; healthy; malignant

Cancer is swiftly becoming the leading cause of death in western populations, and it is estimated that 1 in 2 people born in the U.K. after 1960 will be diagnosed with cancer during their lifetime. Approximately 375,000 new cases of cancer are diagnosed in the U.K. every year (>1,000 per day) and only 50% of those are expected to survive. That equates to more than 450 cancer related deaths per day. Demonstrating a critical need for a better understanding of the underlying biology of cancer and development of new effective therapies.Acute myeloid leukaemia (AML) is a blood cancer with very poor prognosis. Treatment options have remained largely unchanged in the last 30 years, with good initial response to therapy, but high rates of relapse and very poor overall survival. One of the key problems with current therapy is the inability to deplete the cells at the apex of the disease, so called leukaemic stem cells (LSCs). These cells are highly resistant to therapy and are the origins of relapse and ultimately the root cause of poor prognosis in AML.In this fellowship, I will study how the repertoire of proteins (the functional effectors within cells) changes during the transition of healthy blood cells to leukaemia. Using novel models of leukaemic transformation and state-of-the-art proteomic (monitoring all proteins in a cell) techniques I will chart functional changes in the protein biology of primitive blood cells, from the earliest stages of leukaemia development, to the critical mass of frank leukaemia. By comparing healthy and malignant cells side by side, I will uncover key differences that could represent vulnerabilities that are leukaemia specific. Using this approach, it is possible to test new targeting protocols that specifically kill leukaemic cells and preserve healthy cells, in contrast to current chemotherapeutic protocols which kill all growing cells, be they healthy or leukaemic.During this fellowship I will use newly generated data on LSCs alongside previously published data on niche-derived factors to model where LSCs grow and what they require from their niche to evade chemotherapy. This will bring in an extra layer of complexity to the project, which will help account for niche-derived mechanisms which can be the underlying cause of chemotherapeutic evasion. This part of the fellowship will also provide a deep understanding of the bone marrow niche as leukaemia develops and help to find new ways to preserve cells supportive of healthy blood production and selectively deplete cells supportive of leukaemia development.Finally, the information gained from these approaches will be validated in a cohort of primary patient AML samples, which I will curate in collaboration with the haematological research network (hmrn.org) based at York. It is vitally important to test the new biological mechanisms for their relevance in primary human AML, especially as targeting these mechanisms could have clinical impact. Alongside primary patient AML samples, I will work with the Anthony Nolan Research Institute (the largest bone marrow transplantation service in the U.K.) to test how new therapeutic approaches affect healthy blood production and how to avoid killing healthy cells or impeding bone marrow transplantation approaches. This represents a key ethos within my fellowship: to target malignant cells, whilst preserving healthy tissue. Ultimately this provides the opportunity to treat AML in a more targeted and strategic manner, but also offers the opportunity to bring those patients once classified as clinically unfit for intensive chemotherapy (e.g. the elderly), and with a dismal prognosis, back into suitability for more intensive protocols with far superior outcomes.

癌症正在迅速成为西方人口死亡的主要原因，据估计，在英国出生的人中，每2人中就有1人患有癌症。1960年以后的人在他们的一生中都会被诊断出患有癌症。在英国，大约有375，000例新的癌症病例被诊断出来。每年（每天超过1，000人），预计只有50%的人能够生存。这相当于每天有450多人死于癌症。急性髓细胞白血病（AML）是一种预后极差的血液肿瘤，其发病机制是恶性肿瘤的一种，是一种恶性肿瘤，其发病机制是恶性肿瘤的一种。在过去的30年里，治疗选择基本上保持不变，对治疗的初始反应良好，但复发率高，总生存率很低。目前治疗的关键问题之一是无法耗尽疾病顶点的细胞，即所谓的白血病干细胞（LSC）。这些细胞对治疗具有高度抵抗性，是复发的根源，最终是AML预后不良的根本原因。在这个奖学金中，我将研究蛋白质（细胞内的功能效应器）在健康血细胞向白血病转变过程中的变化。使用白血病转化的新模型和最先进的蛋白质组学（监测细胞中的所有蛋白质）技术，我将绘制原始血细胞蛋白质生物学的功能变化，从白血病发展的最早阶段，到坦率的白血病的临界质量。通过并排比较健康和恶性细胞，我将发现可能代表白血病特异性脆弱性的关键差异。使用这种方法，有可能测试新的靶向方案，专门杀死白血病细胞和保护健康的细胞，而不是目前的化疗方案，杀死所有生长的细胞，无论是健康的或leukemia.During这个奖学金我将使用新生成的数据对LSCs和以前发表的数据对利基衍生因子模型LSCs生长和他们需要从他们的利基逃避化疗。这将为该项目带来额外的复杂性，这将有助于解释可能是化疗逃避的根本原因的利基衍生机制。这部分奖学金还将提供对白血病发展过程中骨髓生态位的深入了解，并帮助找到新的方法来保存支持健康血液生成的细胞，并选择性地消耗支持白血病发展的细胞。最后，从这些方法中获得的信息将在一组原发性AML患者样本中得到验证，我将与位于约克的血液学研究网络（hmrn.org）合作策划。测试新的生物学机制在原发性人类AML中的相关性至关重要，特别是因为靶向这些机制可能具有临床影响。除了主要的AML患者样本，我将与安东尼诺兰研究所（英国最大的骨髓移植服务）合作。以测试新的治疗方法如何影响健康的血液生成，以及如何避免杀死健康细胞或阻碍骨髓移植方法。这代表了我的研究团队的一个关键精神：靶向恶性细胞，同时保护健康组织。最终，这提供了以更具针对性和战略性的方式治疗AML的机会，但也提供了使那些曾被归类为临床上不适合强化化疗的患者（例如老年人）以及预后不良的患者重新适合更强化的方案并具有更好的上级结局的机会。

项目成果

The CKS1/CKS2 Proteostasis Axis Is Crucial to Maintain Hematopoietic Stem Cell Function.

• DOI: 10.1097/hs9.0000000000000853
• 发表时间: 2023-03
• 期刊: HemaSphere
• 影响因子: 6.6