Title: Development of oncolytic viruses for treatment of ATRX-deficient paediatric brain and bone tumours
Funder: The Academy of Medical Sciences

Abstract: The aim of the project is the development oncolytic viruses for the treatment of ATRX-deficient glioblastoma and sarcoma in a pre-clinical study. ALT-cancers are tumours that use telomerase-independent mechanisms for immortalization. Loss of ATRX is a central event in the ALT pathway, and so most ALT-cancers are ATRX-deficient. ATRX appears to have multiple cellular roles, including transcriptional regulation, chromatin remodelling, histone deposition at telomeres and processing of abnormal DNA-structures at repetitive regions. In addition, ATRX plays a role in PML-nuclear bodies, which are a critical component of the innate immune response to viral infection. It has been previously shown that ATRX-deficient cells are particularly susceptible to infection by herpes viruses. In this research project, I aim to develop viral therapies for ATRX-deficient tumours - capitalising on their intrinsic susceptibility to viral infection. I would investigate several oncolytic viruses (adenoviruses and herpes viruses) - initially investigating their ability to infect and kill ATRX-deficient tumour cells using cell lines (with ATRX-replete controls for comparison). We would start with several viruses that are already undergoing clinical trial for other cancer types. The viruses with the most promising results would then be selected for further study. I would aim to increase the synthetic lethality of these viruses by inclusion of shRNA which would, again, impede ATRX-deficient cells without affecting normal cells. The overall aim of the project would be to generate an oncolytic virus which could then be moved forward into animal studies and, eventually, clinical trials in sarcoma and glioblastoma.

Lay abstract: A key ability of cancer cells is their ability to endlessly divide - an event called immortalisation. This allows the cancerous tumours to grow more rapidly and larger than any normal cells would be able to do. Some tumours - collectively called ALT cancers - use a pathway called the ALT pathway to achieve immortalisation. Paediatric brain tumours and bone tumours are usually ALT cancers - both of these cancers are difficult to treat and often incurable. The majority of ALT-tumours lack a particular protein called ATRX. ATRX carries out many important functions within normal cells - including defence against viral infection. Cells that lack ATRX are, therefore, particularly susceptible to infection by viruses. In this project, I would take advantage of this susceptibility, in order to make novel treatments for ALT-cancers, in particular paediatric brain and bone tumours. The first stage of the work would be testing a range of different viruses in ATRX-deficient ALT cancer cell lines and paired normal cell lines (cells growing in a laboratory). This should lead to identification of viruses that predominantly infect cancerous cells, without effectively infecting normal cells. The second stage of the work would be further manipulating the most effective viruses, in order to increase their lethality to cancerous cells.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS