New therapeutic strategies for brain tumours: mechanistic analysis of Zika-driven medulloblastoma oncolysis

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.