A living biobank of post-surgical residual glioblastoma to replace animal studies

点击翻译按钮获取中文摘要

Animals in research generally do not receive the full spectrum of therapy that is standard-of-care for patients, since surgical resection of tumours in rodent models is technically challengingand unproven. Therefore, it is unclear whether survival gains in animal models reflect treatmentresponse within the core mass of the tumour, or the highly infiltrative margin. This is clinicallyrelevant, as in patients receiving standard treatment, only the infiltrative residual cells left behindafter surgery are responsible for disease progression. Consequently, we aim to establish a 3-dimensional living biobank of glioblastoma which reflects the spectrum of resected and residualdisease in human patients, and demonstrate its utility as a highly-characterised, efficient andclinically relevant alternative to animal studies.Objectives:1. Generate and characterise 15-20 (4 generated at present) paired GSC lines from the tumourcore and adjacent infiltrated brain of surgical specimens to comprehensively model resected andresidual disease, respectively (in addition to 15-20 further GSC lines where only resecteddisease is available).- This objective will incorporate comparison of response to conventional treatment in the livingbiobank & corresponding patients to establish how well these models predict therapeuticresponse in human patients.2. Complete detailed functional comparison of cellular responses to IR and temozolomide (TMZ)chemotherapy and contrast the associated transcriptomic landscapes between resected andresidual disease.3. Provide proof-of-principle data that the living biobank can be used to identify new therapeuticcombinations which effectively target post-surgical residual disease - small molecules whichtarget the DDR will be used as an example since current patient treatment is based on DNA damaging agents (chemo- & radiotherapy).