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Towards new therapeutic strategies: Zika-driven oncolysis of brain tumor cells

迈向新的治疗策略：寨卡驱动的脑肿瘤细胞溶瘤

基本信息

批准号：
MR/S01411X/1
负责人：
Robert Michael Ewing
金额：
$ 19.32万
依托单位：
University of Southampton
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2018
资助国家：
英国
起止时间：
2018 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FS01411X%2F1
关键词：
Towards new therapeutic strategies Zika

项目摘要

Brain tumours are amongst the most complicated and expensive types of cancer to treat. Brain tumour cells are typically highly aggressive and invasive, and the available treatment options may not be successful and often have side-effects which leave surviving patients with chronic long-term illnesses or disabilities. The occurrence of CNS tumours are rising in many countries, and Latin American countries such as Brazil now have some of the highest rates of occurrence of these types of cancer. In addition, in many Low and Middle Income Countries (LMICs) such as Brazil, there is very high income inequality which is often associated with disparities in access to proper healthcare; brain cancers require sophisticated and long term treatments and access to appropriate, let alone leading-edge treatments can be highly variable. In this project, our goal is to develop a new therapy against brain tumours called oncolytic viral therapy. This type of anti-tumour therapy makes use of viruses which are able to very specifically infect and destroy cancer cells. Although this type of therapy has been successfully developed for other types of cancer, oncolytic viral therapy has not yet been applied to brain cancers. This project builds on a recent finding made at the University of Sao Paulo in Brazil whereby the Zika virus is able to infect and destroy specific types of brain cancer cell. Zika virus is best known as an infectious mosquito-borne virus that can cause developmental defects in the brains of babies born to women with Zika infection. Brazil has been at the centre of this public health crisis, and much has been learned about how the Zika virus does this over the last few years. The recent discovery of the potential of Zika as a therapeutic agent against brain cancers now raises important questions that we will address in this project. In common with other pathogenic viruses, Zika invades human host cells and then uses the host cell machinery to replicate and produce more virus particles. How this happens in brain tumour cells is entirely unknown. This project aims to understand how proteins produced by the Zika virus interact and control proteins in the host human cells. Preliminary studies have indicated that certain types of brain cancer cell are susceptible to the Zika virus, and others less so. We aim to discover why this is so, and what the specific signatures of susceptible brain tumour cells are. In terms of a future oncolytic viral therapy, answering these questions will allow us to (1) design therapeutics that mimic Zika and (2) understand which brain tumours are best suited to the new therapy, thereby targeting the therapy to those patients who can benefit most. If successful, our project will contribute towards the development of a new therapeutic option that can be used to treat patients with one of the most aggressive forms of cancer. By design, our project will be a collaboration between the University of Sao Paulo, where this discovery was initially made and the University of Southampton. Specific "proteomic" techniques which allow the highly sensitive measurement of thousands of proteins in human cells are used at the University of Southampton, and through this collaboration this technique will be applied to develop Zika as an oncolytic therapy. In addition, cross-training of early career researchers between the partner laboratories will allow the exchange of expertise, and in particular the training of Brazilian researchers in proteomic techniques, an important and very powerful approach with the potential to impact many other biomedical research areas.

脑肿瘤是治疗最复杂、最昂贵的癌症之一。脑肿瘤细胞通常具有很强的侵袭性和侵袭性，现有的治疗方案可能不成功，而且往往有副作用，使幸存的患者患有慢性长期疾病或残疾。在许多国家，中枢神经系统肿瘤的发病率正在上升，而巴西等拉丁美洲国家目前是这类癌症发病率最高的国家之一。此外，在许多低收入和中等收入国家（如巴西），存在着非常严重的收入不平等，这往往与获得适当医疗保健方面的差距有关；脑癌需要复杂和长期的治疗，并获得适当的治疗，更不用说先进的治疗方法了，可能会有很大的变化。在这个项目中，我们的目标是开发一种新的治疗脑肿瘤的方法，叫做溶瘤病毒疗法。这种类型的抗肿瘤疗法利用能够非常特异性地感染和破坏癌细胞的病毒。尽管这种疗法已经成功地应用于其他类型的癌症，但溶瘤病毒疗法尚未应用于脑癌。该项目基于巴西圣保罗大学最近的一项发现，即寨卡病毒能够感染并破坏特定类型的脑癌细胞。寨卡病毒是一种传染性的蚊子传播病毒，可以导致感染寨卡病毒的妇女所生婴儿的大脑发育缺陷。巴西一直处于这场公共卫生危机的中心，在过去几年里，人们对寨卡病毒是如何造成这种情况有了很多了解。最近发现的寨卡病毒作为脑癌治疗药物的潜力，现在提出了我们将在这个项目中解决的重要问题。与其他致病性病毒一样，寨卡病毒侵入人类宿主细胞，然后利用宿主细胞机制进行复制并产生更多的病毒颗粒。这在脑肿瘤细胞中是如何发生的完全未知。该项目旨在了解寨卡病毒产生的蛋白质如何相互作用并控制宿主人类细胞中的蛋白质。初步研究表明，某些类型的脑癌细胞对寨卡病毒敏感，而其他类型的细胞则不那么敏感。我们的目标是发现为什么会这样，以及易感脑肿瘤细胞的具体特征是什么。就未来的溶瘤病毒治疗而言，回答这些问题将使我们能够：(1)设计出模仿寨卡病毒的治疗方法；(2)了解哪种脑肿瘤最适合这种新疗法，从而将治疗目标锁定在那些受益最大的患者身上。如果成功，我们的项目将有助于开发一种新的治疗选择，可用于治疗最具侵略性的癌症之一的患者。根据设计，我们的项目将是圣保罗大学和南安普敦大学之间的合作，这一发现最初是在圣保罗大学发现的。南安普顿大学使用了特定的“蛋白质组学”技术，可以高度敏感地测量人类细胞中的数千种蛋白质，通过这次合作，这项技术将被应用于开发寨卡病毒作为一种溶瘤疗法。此外，在伙伴实验室之间对早期职业研究人员进行交叉培训将有助于交流专门知识，特别是对巴西研究人员进行蛋白质组学技术方面的培训，这是一种重要和非常有力的方法，有可能影响许多其他生物医学研究领域。