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

MICA：确定靶向 mTORC-1/2 在慢性淋巴细胞白血病中的治疗潜力 - 一项临床前研究

• 批准号: MR/K014854/1
• 负责人: Alison Michie
• 金额: $ 61.83万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK014854%2F1
• 关键词: MICA; Determining; therapeutic; potential; targeting

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.

慢性淋巴细胞白血病（CLL）是英国最常见的血癌，目前化疗无法治愈。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重新出现，所有患者最终都会复发。对于复发患者尚无明确的二线治疗计划，这突显了 CLL 中对额外治疗方案的医疗需求未得到满足。现在人们普遍认为，CLL 中的白血病 B 细胞与患者淋巴器官（淋巴结和骨髓）内的几种支持细胞相互作用；这些细胞向白血病细胞提供生存和生长信号，多项研究表明，这些关联会阻止目前​​使用的化疗药物在患者中发挥最大效果。我们假设一种名为 mTor 的特殊蛋白质在其他人类癌症中通常失调，它在调节负责维持 CLL 细胞保护和存活并促进疾病进展的关键蛋白质方面发挥着核心作用。事实上，我们的初步数据支持了这一假设，证实 mTor 在源自血液或淋巴结的原代 CLL 细胞以及源自 CLL 小鼠模型的细胞中均具有活性。此外，我们还确定，当 CLL 细胞暴露于淋巴器官中存在的微环境信号时，mTor 会进一步激活。我们的研究表明，有必要进一步研究分析 mTor 在 CLL 细胞存活和增殖中的作用，因为它可能代表 CLL 中一个有前途的药物靶点。我们开发了强大的实验方法，包括在培育微环境中体外培养人类 CLL 细胞，复制患者淋巴结中收到的信号，以及在体内密切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，并探索使用已在实体瘤恶性肿瘤临床测试的高选择性 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 在 CLL 患者来源的淋巴器官中是否活跃；3 - 使用选择性抑制剂确定 mTor 抑制如何影响 CLL 小鼠模型体内的疾病进展。总的来说，拟议的研究将确定 mTor 抑制是否代表 CLL 的有效药物靶点，从而获得有价值的结果 可为未来 CLL 临床试验的设计提供信息。此外，对 mTor 在调节 CLL 细胞增殖和存活中所发挥的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），这将使临床医生能够将患者分为亚组，识别那些对 CLL 和其他癌症类型的 mTor 靶向治疗有良好反应的患者。

项目成果

The role of mTOR-mediated signals during haemopoiesis and lineage commitment.

• DOI: 10.1042/bst20180141
• 发表时间: 2018-10-19
• 期刊: Biochemical Society transactions
• 影响因子: 3.9
• 作者: Malik N;Sansom OJ;Michie AM
• 通讯作者: Michie AM

Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells.

• DOI: 10.1038/nature18288
• 发表时间: 2016-06-16
• 期刊: Nature
• 影响因子: 64.8
• 作者: Abraham SA;Hopcroft LE;Carrick E;Drotar ME;Dunn K;Williamson AJ;Korfi K;Baquero P;Park LE;Scott MT;Pellicano F;Pierce A;Copland M;Nourse C;Grimmond SM;Vetrie D;Whetton AD;Holyoake TL
• 通讯作者: Holyoake TL

Targeting quiescent leukemic stem cells using second generation autophagy inhibitors.

• DOI: 10.1038/s41375-018-0252-4
• 发表时间: 2019-04
• 期刊: Leukemia
• 影响因子: 11.4
• 作者: Baquero P;Dawson A;Mukhopadhyay A;Kuntz EM;Mitchell R;Olivares O;Ianniciello A;Scott MT;Dunn K;Nicastri MC;Winkler JD;Michie AM;Ryan KM;Halsey C;Gottlieb E;Keaney EP;Murphy LO;Amaravadi RK;Holyoake TL;Helgason GV
• 通讯作者: Helgason GV

Targeting mitochondrial oxidative phosphorylation eradicates therapy-resistant chronic myeloid leukemia stem cells.

• DOI: 10.1038/nm.4399
• 发表时间: 2017-10
• 期刊: Nature medicine
• 影响因子: 82.9
• 作者: Kuntz EM;Baquero P;Michie AM;Dunn K;Tardito S;Holyoake TL;Helgason GV;Gottlieb E
• 通讯作者: Gottlieb E