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

慢性淋巴细胞白血病（CLL）是英国最常见的血液癌症，目前无法用化疗治愈。在每年3000例新诊断中，三分之二的患者最终需要治疗，虽然这些患者中的大多数最初对当前的一线化疗有反应，但由于逃避初始治疗的白血病细胞的重新出现，所有患者最终都会复发。对于复发患者，没有明确的二线治疗计划，突出了CLL中对其他治疗选择的未满足的医疗需求。现在公认的是，CLL中的白血病B细胞与患者淋巴器官内的几种类型的支持细胞相互作用（淋巴结和骨髓）;这些细胞为白血病细胞提供存活和生长信号，几项研究表明，这些关联阻止了目前使用的化疗剂在患者中发挥最大作用。我们假设一种称为mTor的特定蛋白质在其他人类癌症中通常被解除调控，在调节负责维持CLL细胞保护和存活并促进疾病进展的关键蛋白质方面起着核心作用。事实上，我们的初步数据支持这一假设，确立mTor在来源于血液或淋巴结的原代CLL细胞和来源于CLL小鼠模型的细胞中均具有活性。此外，我们建立了mTor被进一步激活时，CLL细胞暴露于淋巴器官中存在的微环境信号。我们的调查表明，进一步的研究分析mTor在CLL细胞的生存和增殖的作用是必要的，因为它可能代表一个有前途的药物靶点在CLL.We已经开发了强大的实验方法，涉及在培养的微环境中，复制在患者淋巴结中收到的信号，和CLL小鼠模型，密切复制先进的人类疾病在体内的人类CLL细胞的体外培养。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，并探索使用已在临床上测试的高选择性mTor抑制剂治疗抑制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是否在源自CLL患者的淋巴器官中有活性; 3 -确定使用选择性抑制剂的mTor抑制如何影响体内CLL小鼠模型中的疾病进展。总的来说，所提出的研究将确定mTor抑制是否代表CLL中的有效药物靶点，获得有价值的信息，可以为未来的CLL临床试验设计提供信息。此外，对mTor在调节CLL细胞增殖和存活中所起作用的基本理解可能有助于发现新的蛋白质标志物（生物标志物），这将使临床医生能够将患者分为亚组，识别那些对mTor靶向治疗反应良好的患者，无论是在CLL还是其他癌症类型中。

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.