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

由于在啮齿动物模型中手术切除肿瘤在技术上具有挑战性且未经证实，因此研究中的动物通常不会接受患者标准护理的全套治疗。因此，尚不清楚动物模型中的生存提高是否反映了肿瘤核心肿块内的治疗反应，还是高度浸润的边缘。这与临床相关，因为在接受标准治疗的患者中，只有手术后留下的浸润性残留细胞才是导致疾病进展的原因。因此，我们的目标是建立一个三维胶质母细胞瘤活生物库，它反映了人类患者切除和残留疾病的频谱，并证明其作为一种高度表征、高效和临床相关的替代动物研究的实用性。从手术标本的肿瘤核心和邻近浸润脑中生成15-20（目前生成4）对GSC细胞系并对其进行表征，分别对切除和残留疾病进行全面建模（此外还有15-20个仅可获得切除疾病的GSC细胞系）。-该目标将包括比较活体生物库和相应患者对常规治疗的反应，以确定这些模型预测人类患者治疗反应的效果。完成对IR和替莫唑胺（TMZ）化疗的细胞反应的详细功能比较，并对比切除和残留疾病之间相关的转录组景观。提供原理证明数据，证明活体生物库可用于识别有效靶向术后残留疾病的新治疗组合-靶向DDR的小分子将被用作示例，因为目前的患者治疗基于DNA损伤剂（化疗和放疗）。

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).