MICA: Determining the therapeutic potential of targeting mTORC-1/2 in chronic lymphocytic leukaemia - a pre-clinical study

慢性淋巴细胞性白血病(CLL)是英国最常见的血癌，目前无法通过化疗治愈。在每年的3000例新诊断中，三分之二的患者最终将需要治疗，虽然这些患者中的大多数最初对目前的一线化疗有反应，但由于逃避初步治疗的白血病细胞重新出现，最终全部复发。目前还没有针对复发患者的明确的二线治疗计划，这突显了CLL中对额外治疗选择的医疗需求尚未得到满足现在公认的是，CLL中的白血病B细胞与患者淋巴器官(淋巴和骨髓)内的几种类型的支持细胞相互作用；这些细胞为白血病细胞提供生存和生长信号，多项研究表明，这些关联阻止了目前使用的化疗药物在患者身上发挥最大效果。我们假设，一种名为mTOR的特定蛋白质在调节负责维持CLL细胞保护和生存并促进疾病进展的关键蛋白质方面发挥核心作用，这种蛋白质在其他人类癌症中通常被解除调控。事实上，我们的初步数据支持这一假设，证实mTOR在来源于血液或淋巴结的原代CLL细胞和来源于CLL小鼠模型的细胞中都是活跃的。此外，我们证实，当CLL细胞暴露在淋巴器官中的微环境信号中时，mTOR进一步激活。我们的研究表明，进一步分析mTOR在CLL细胞存活和增殖中的作用是必要的，因为它可能是CLL的一个有前途的药物靶点。我们已经开发出强大的实验方法，包括在培养微环境中复制患者淋巴结中接收到的信号的人CLL细胞的体外培养，以及在体内紧密复制晚期人类疾病的CLL小鼠模型。通过这些模型系统，我们将阐明mTOR在CLL维持和进展中的作用，并探索使用已经在实体肿瘤临床上测试的高选择性mTOR抑制剂来治疗抑制mTOR介导的信号的途径。因此，我们将：1-检查抑制mTOR对CLL细胞存活和增殖的影响；2-确定mTOR在CLL患者的淋巴器官中是否活跃；3-确定使用选择性抑制剂抑制mTOR如何影响活体CLL小鼠模型的疾病进展。综合而言，拟议的研究将确定mTOR抑制是否代表CLL的有效药物靶点，获得有价值的信息，为未来CLL临床试验的设计提供参考。此外，对mTOR在调节CLL细胞增殖和存活中所起作用的基本了解可能有助于发现新的蛋白质标记物(生物标记物)，使临床医生能够将患者分成不同的亚组，识别哪些患者对mTOR靶向治疗效果良好，无论是在CLL还是其他癌症类型。

Chronic lymphocytic leukaemia (CLL) is the most common blood cancer in the UK and is currently incurable with chemotherapy. Of the 3000 new diagnoses/year, two thirds of patients will eventually require treatment, and while the majority of these patients initially respond to current first-line chemotherapy, all eventually relapse due to the re-emergence of leukaemic cells that evaded initial treatment. There is no defined second-line treatment plan for relapsed patients, highlighting the unmet medical need for additional therapeutic options in CLLIt is now accepted that the leukaemic B cells in CLL interact with several types of supportive cells within patient lymphoid organs (lymph nodes and bone marrow); these cells provide survival and growth signals to the leukaemic cells, and several studies demonstrate that these associations prevent currently used chemotherapy agents from delivering maximal effect in the patient. We hypothesise that one particular protein called mTor, which is commonly deregulated in other human cancers, plays a central role in regulating key proteins responsible for maintaining CLL cell protection and survival and promotes disease progression. Indeed, our preliminary data support this hypothesis, establishing that mTor is active both in primary CLL cells derived from the blood or lymph node, and cells derived from a CLL mouse model. Moreover we establish that mTor is further activated when CLL cells are exposed to microenvironmental signals present in the lymphoid organs. Our investigations indicate that further studies analysing the role of mTor in CLL cell survival and proliferation are warranted, as it may represent a promising drug target in CLL.We have developed powerful experimental approaches involving the in vitro culture of human CLL cells in nurturing microenvironments that replicate the signals received in patient lymph nodes, and CLL mouse models that closely replicate advanced human disease in vivo. With these model systems we will elucidate the role of mTor in maintenance and progression of CLL and explore avenues for therapeutic inhibition of mTor-mediated signals, using highly selective mTor inhibitors that have already been tested in the clinic for solid tumour malignancies. Therefore we will:1 - Examine the impact of inhibiting mTor on CLL cell survival and proliferation;2 - Define whether mTor is active in lymphoid organs derived from CLL patients;3 - Determine how mTor inhibition, using selective inhibitors, influences disease progression in CLL mouse models in vivo.Collectively, the proposed studies will establish whether mTor inhibition represents a valid drug target in CLL, gaining valuable information that could inform the design of future clinical trials in CLL. Moreover, a fundamental understanding of the role played by mTor in regulating CLL cell proliferation and survival may assist in the discovery of novel protein markers (biomarkers) that will enable clinicians to stratify patients into subgroups, identifying those patients that would respond well to mTor-targeted therapies, both in CLL and other cancer types.