Rationalizing responses to Aurora B inhibitors in leukaemia

急性髓系白血病(AML)是最常见的急性白血病形式，对大多数患者来说仍然是无法治愈的。基于激酶抑制剂的新的靶向治疗正在急性髓细胞白血病中进行测试，但并不是所有的患者都能获得相同程度的好处，这突显了个性化治疗的必要性。以前的工作已经显示出Aurora B抑制剂在AML中的应用前景。在这里，学生将采用蛋白质组学和系统生物学的方法来研究AML细胞对Aurora B靶向治疗敏感的机制。除了促进我们对Aurora B在癌症生物学中作用的理解，这项工作还有可能影响AML的个性化治疗。Aurora激酶在癌症生物学中发挥着突出的作用(参考文献1)，评估Aurora B抑制剂在急性髓系白血病(AML)中的临床试验显示出希望。然而，并不是所有的患者对这些治疗的反应都是相同的，允许癌细胞逃避治疗的机制还没有完全了解。该项目的目的是研究Aurora B抑制剂在AML细胞中的作用模式，以及使癌细胞对这些化合物敏感或耐药的生化机制。为此，学生将比较不同敏感性的细胞系中生化网络对Aurora B抑制剂的连接，并研究这种生化连接在治疗后发生了怎样的变化。这将通过使用最先进的蛋白质组和磷蛋白质组学方法与计算方法相结合来实现，以从这些数据集得出生化网络拓扑。这些方法在宿主实验室得到了很好的开发，它们在不同癌症模型中的应用表明，对激酶抑制剂的反应由靶通路和平行通路的活性共同决定(参考文献2-5)。最初以细胞为基础的工作产生的假设将在其他AML细胞系、从BCI组织生物库获得的初级AML样本以及从Aurora B抑制剂当前和计划的AML临床试验中获得的样本中进行测试。除了提高我们对Aurora B如何控制癌症生物学的理解外，与患者反应相关的签名可能代表患者分层和个性化药物的生物标记物。该项目将培训学生基于质谱学的蛋白质组学和计算生物学应用于细胞内细胞信号研究和癌症研究。这些独特的技能组合在英国供不应求，受到工业界和学术界的高度重视。

Acute myeloid leukaemia (AML), the most common form of acute leukaemia, remains incurable for most patients. New targeted therapies based on kinase inhibitors are being tested in AML, but not all patients benefit to the same extent, highlighting the need for personalized treatments. Previous work has shown promise for Aurora B inhibitors in AML. Here, the student will take proteomic and system biology approaches to investigate the mechanisms that sensitize AML cells to Aurora B targeted therapy. In addition to advancing our understanding of Aurora B role in cancer biology, this work has the potential to impact AML personalized therapy.Aurora kinases play prominent roles in cancer biology (Ref 1) and clinical trials evaluating Aurora B inhibitors in acute myeloid leukaemia (AML) are showing promise. However, not all patients respond to these therapies to the same extent and the mechanisms that allow cancer cells to evade treatment are not fully understood. The aim of this project is to investigate the mode of action of Aurora B inhibitors in AML cells and the biochemical mechanisms that make cancer cells sensitive or resistant to these compounds. To this end, the student will compare the wiring of biochemical networks in cell lines of different sensitivity profile to Aurora B inhibitors and will investigate how such biochemical wiring changes upon therapy. This will be achieved by using state-of-the-art proteomic and phosphoproteomic methods in combination with computational approaches to derive biochemical network topology from such datasets. These methodologies are well developed in the host laboratory and their application in different cancer models has shown that responses to kinase inhibitors are determined by the combination of the activity of both the target and parallel pathways (Refs 2-5). The hypotheses generated with the initial cell-based work will be tested in additional AML cell lines, primary AML samples obtained from the BCI tissue biobank and in those derived from current and planned Aurora B inhibitors clinical trials in AML. In addition to advancing our understanding of how Aurora Bcontrols cancer biology, signatures associated with patient responses may represent biomarkers for patient stratification and personalized medicine.The project will train the student in mass spectrometry-based proteomics and computational biology applied to the investigation of intracellular cell signaling and cancer research. These unique combination of skills are in short supply in the UK and are highly valued by industry and academia.