Investigating the importance of translation elongation in B cell malignancies through modulation of the eEF2K/eEF2 signalling axis.

通过调节 eEF2K/eEF2 信号轴研究翻译延伸在 B 细胞恶性肿瘤中的重要性。

• 批准号: MR/X008169/1
• 负责人: Alison Michie
• 金额: $ 83.39万
• 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: 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%2FX008169%2F1
• 关键词: Investigating; importance; translation; elongation; cell

Title: Teaching old drugs new tricks: can blood cancer patients benefit from repurposed drugs?Non-Hodgkin lymphomas (NHL) are a group of white blood cell cancers that mainly affect cells called B lymphocytes (B-NHL). These cancers represent ~4% of all cancers diagnosed in the UK annually (~14,000 cases/year). The treatments available for NHL patients still rely heavily on chemotherapy which can generate significant toxic side effects in all patients and can be too toxic for unfit or elderly patients to tolerate, due to additional underlying health problems such as heart conditions. Furthermore, patients can become develop resistance to the drugs. This results in the disease re-emerging (relapsing) due to cancer cells escaping initial treatment. Indeed 30-40% of patients with the commonest form of B-NHL relapse after treatment, representing a particular unmet clinical need. There is a requirement for new targeted treatments for NHL patients. In addition to developing better treatments, it is important that drugs are given to appropriate patients, providing personalised treatments. To ensure that this happens, molecular markers (biomarkers) can be developed that identify the patients that will benefit from specific treatments. In this way we will enhance the clinical management and survival prospects of B-NHL patients.When normal cells become cancerous, they deregulate the processes controlling energy production to satisfy their increased need to fuel uncontrolled growth. One of the processes that requires significant amounts of energy is protein synthesis, the ability of cells to make new proteins. These newly generated proteins are responsible for driving disease progression increasing cell survival and replication. Our studies have identified that a protein called elongation factor-2 kinase (EF2K), normally responsible for inhibiting protein synthesis, is switched off in aggressive blood cancer cells, thus letting protein synthesis proceed in an uncontrolled manner. Our data show that EF2K in blood cancer cells is particularly sensitive to an established drug rapamycin, resulting in a reduction in disease progression. Furthermore, we have identified a drug called nelfinavir, originally approved to treat HIV patients in 1997, that has anti-cancer activities at least in part through the activation of EF2K. While nelfinavir is in clinical trials in breast, kidney lung cancers, the clinical activity of nelfinavir has not been tested in B-NHL. Therefore we will: I. Determine whether EF2K is essential for the development of blood cancers by genetically altering blood cancer cells from mice or human patients, and testing the cells ability to grow and survive in our laboratory models;II. Identify which specific types of B-NHL patients would benefit from EF2K targeting treatments by screening a range of B-NHL patient samples, featuring slow-growing and aggressive cancers, to test EF2K activity;III. Establish whether drugs that activate of EF2K represent a valid therapeutic strategy blood cancer patients by conducting drug tests in our models and comparing the ability of rapamycin or nelfinavir to reduce or eradicate disease. IV. Discover potential new drug targets that are regulated by EF2K-mediated protein synthesis and responsible for driving blood cancer progression by performing detailed analyses of human- and mouse-derived blood cancer cells and testing whether these new targets are responsive to rapamycin or nelfinavir treatment. As EF2K has been shown to play an central role in the regulation of a number of different diseases involving learning and memory, heart and many cancers, the results generated in this proposal will be of use to a number of fields in addition to blood cell cancers. This study will also provide us with important information about how to develop nelfinavir, a safe oral drug, for use in human B-NHL clinical trials in the future.

原标题：教授老药新把戏：血癌患者能从再利用的药物中获益吗？非霍奇金淋巴瘤（NHL）是一组主要影响称为B淋巴细胞（B-NHL）的细胞的白色血细胞癌症。这些癌症占英国每年诊断的所有癌症的约4%（约14，000例/年）。可用于NHL患者的治疗仍然严重依赖于化疗，化疗可在所有患者中产生显著的毒副作用，并且由于其他潜在的健康问题如心脏病，化疗对于不适合或老年患者来说毒性太大而无法耐受。此外，患者可能会对药物产生耐药性。这导致由于癌细胞逃避初始治疗而导致疾病重新出现（复发）。事实上，30-40%的最常见形式的B-NHL患者在治疗后复发，这代表了一种特殊的未满足的临床需求。NHL患者需要新的靶向治疗。除了开发更好的治疗方法外，重要的是将药物给予适当的患者，提供个性化治疗。为了确保这种情况发生，可以开发分子标记物（生物标志物）来识别将从特定治疗中受益的患者。通过这种方式，我们将提高B-NHL患者的临床管理和生存前景。当正常细胞癌变时，它们会放松控制能量产生的过程，以满足其增加的需求，为不受控制的生长提供燃料。需要大量能量的过程之一是蛋白质合成，即细胞制造新蛋白质的能力。这些新产生的蛋白质负责驱动疾病进展，增加细胞存活和复制。我们的研究已经确定，一种称为延伸因子-2激酶（EF 2K）的蛋白质，通常负责抑制蛋白质合成，在侵袭性血液癌细胞中被关闭，从而使蛋白质合成以不受控制的方式进行。我们的数据表明，血液癌细胞中的EF 2K对已确定的药物雷帕霉素特别敏感，从而减少疾病进展。此外，我们已经确定了一种名为nelfinavir的药物，最初于1997年被批准用于治疗HIV患者，该药物至少部分通过激活EF 2K而具有抗癌活性。虽然奈非那韦在乳腺癌、肾癌和肺癌的临床试验中，但奈非那韦的临床活性尚未在B-NHL中进行测试。因此，我们将：通过遗传改变小鼠或人类患者的血液癌细胞，并在我们的实验室模型中测试细胞生长和存活的能力，确定EF 2K是否对血液癌的发展至关重要;II.通过筛选一系列以缓慢生长和侵袭性癌症为特征的B-NHL患者样品以测试EF 2K活性来鉴定哪些特定类型的B-NHL患者将受益于EF 2K靶向治疗;III.通过在我们的模型中进行药物试验并比较雷帕霉素或奈非那韦减少或根除疾病的能力，确定激活EF 2K的药物是否代表血液癌症患者的有效治疗策略。四.通过对人和小鼠来源的血癌细胞进行详细分析，并测试这些新靶点是否对雷帕霉素或奈非那韦治疗有反应，发现受EF 2K介导的蛋白质合成调控并负责推动血癌进展的潜在新药靶点。由于EF 2K已被证明在许多涉及学习和记忆，心脏和许多癌症的不同疾病的调节中发挥核心作用，因此该提案中产生的结果将用于除血细胞癌症之外的许多领域。这项研究也将为我们提供重要的信息，如何开发奈非那韦，一个安全的口服药物，用于人类B-NHL的临床试验在未来。

项目成果

mTORC1-selective activation of translation elongation promotes disease progression in chronic lymphocytic leukemia.

• DOI: 10.1038/s41375-023-02043-3
• 发表时间: 2023-12
• 期刊: LEUKEMIA
• 影响因子: 11.4
• 作者: Malik, Natasha;Hay, Jodie;Almuhanna, Hassan N. B.;Dunn, Karen M.;Lees, Jamie;Cassels, Jennifer;Li, Jiatian;Nakagawa, Rinako;Sansom, Owen J.;Michie, Alison M.
• 通讯作者: Michie, Alison M.

The discrete roles of individual FOXO transcription factor family members in B-cell malignancies.

• DOI: 10.3389/fimmu.2023.1179101
• 发表时间: 2023
• 期刊: Frontiers in immunology
• 影响因子: 7.3