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

脑肿瘤是治疗最复杂和最昂贵的癌症类型之一。脑肿瘤细胞通常具有高度侵袭性和侵入性，现有的治疗方案可能不成功，而且往往有副作用，使幸存的患者患上慢性长期疾病或残疾。中枢神经系统肿瘤的发生率在许多国家都在上升，巴西等拉丁美洲国家现在是这些类型癌症发生率最高的国家。此外，在许多低收入和中等收入国家（LMICs），如巴西，存在非常高的收入不平等，这通常与获得适当医疗保健的差距有关;脑癌需要复杂和长期的治疗，获得适当的治疗，更不用说先进的治疗方法了。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，称为溶瘤病毒疗法。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。虽然这种类型的治疗已成功开发用于其他类型的癌症，溶瘤病毒治疗尚未应用于脑癌。该项目建立在巴西圣保罗大学最近的一项发现的基础上，该发现表明寨卡病毒能够感染和破坏特定类型的脑癌细胞。寨卡病毒是一种由蚊子传播的传染性病毒，可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，在过去几年中，人们对寨卡病毒是如何做到这一点的了解很多。最近发现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复制并产生更多病毒颗粒。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在宿主人类细胞中相互作用和控制蛋白质。初步研究表明，某些类型的脑癌细胞易受寨卡病毒感染，而其他类型的则不那么容易感染。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。就未来的溶瘤病毒疗法而言，回答这些问题将使我们能够（1）设计模拟寨卡病毒的疗法，（2）了解哪些脑肿瘤最适合新疗法，从而将治疗靶向那些受益最大的患者。如果成功，我们的项目将有助于开发一种新的治疗选择，可用于治疗患有最具侵袭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顿大学之间的合作，这一发现最初是在那里发现的。南安普顿大学使用了特定的“蛋白质组学”技术，可以高度灵敏地测量人类细胞中的数千种蛋白质，通过这种合作，这种技术将被应用于开发寨卡病毒作为溶瘤疗法。此外，合作实验室之间的早期职业研究人员的交叉培训将允许交流专业知识，特别是对巴西研究人员进行蛋白质组学技术培训，这是一种重要和非常强大的方法，有可能影响许多其他生物医学研究领域。

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.