Are Rab GTPases therapeutic targets in paediatric brain tumours?

脑肿瘤是儿童癌症相关死亡的主要原因之一。虽然手术、放疗和化疗提高了生存率，但这些肿瘤仍然导致许多患者死亡。此外，许多幸存者遭受这些治疗的长期副作用。因此，需要更好地了解这些肿瘤疾病的分子基础，以改善患者的治疗和生存。Rab gtp酶是一大家族的小gtp酶，控制所有真核生物的囊泡出芽，运动和融合。许多研究已经将Rab功能障碍与癌症进展和转移联系起来，尽管它们在儿童脑肿瘤中的作用尚未明确。在其他肿瘤类型中，Rab功能障碍与蛋白酶分泌增加、生长因子受体再循环到质膜和外泌体分泌有关，所有这些都与预后不良和疾病进展有关。该项目的目的是验证特定的Rab gtpase调节囊泡运输途径的假设，这些途径有助于儿科脑肿瘤的发病机制，重点是室管膜瘤和高级胶质瘤（包括多形性胶质母细胞瘤（GBM），间变性星形细胞瘤和弥漫性脑桥固有胶质瘤（DIPG））。休谟博士和科伊尔博士已经共同指导了两名博士生，他们正在研究儿童脑癌髓母细胞瘤中膜转运紊乱的作用。休谟博士和科伊尔博士的实验室专注于了解Rabs在膜运输途径中的作用以及儿科脑肿瘤的基础和治疗。这个项目提供了一个机会来解决一个重要的生物学问题，目的是改善对被诊断患有这些毁灭性肿瘤的儿童的治疗。目的:1。鉴定表达与儿童脑肿瘤预后相关的Rabs；室管膜瘤和高级胶质瘤。2. 确定这些Rabs在肿瘤细胞生物学和病理学中的作用。3. 目的：抑制Rab特异性gtpase的功能，观察其对肿瘤细胞增殖和转移的影响。

Brain tumours are among the leading causes of cancer-related deaths in children. While surgery, radiotherapy and chemotherapy have increased survival rates these tumours still cause many deaths among patients. In addition, many survivors suffer long-term side effects from these treatments. Thus, greater understanding of the molecular basis of disease in these tumours is needed in order to improve patient treatment and survival. Rab GTPases are a large family of small GTPases that control vesicle budding, motility and fusion in all eukaryotes. Many studies have linked Rab dysfunction with cancer progression and metastasis, although their role in paediatric brain tumour has yet to be defined. In other tumour types, Rab dysfunction is associated with increased protease secretion, growth factor receptor recycling to the plasma membrane and exosome secretion, all of which are linked to poor prognosis and disease progression. The aim of this project is to test the hypothesis that specific Rab GTPases regulate vesicle trafficking pathways that contribute to the pathogenesis of paediatric brain tumours focusing on ependymoma and high-grade gliomas (including glioblastoma multiforme (GBM), anaplastic astrocytoma and diffuse intrinsic pontine glioma (DIPG)). Drs Hume and Coyle already co-supervise two PhD students investigating the involvement of disordered membrane transport the paediatric brain cancer medulloblastoma. Drs Hume and Coyle's labs are focussed on understanding the role of Rabs in membrane trafficking pathways and the basis and treatment of paediatric brain tumours. This project offers an opportunity to address an important biological question with the aim of improving the treatment for children diagnosed with these devastating tumours. Aims: 1. To identify Rabs whose expression is linked to outcome in paediatric brain tumours; ependymoma and high-grade glioma. 2. To identify the role of these Rabs tumour cell biology and pathology. 3. To inhibit the function of specific Rab GTPases and look at their effect on tumour cell proliferation and metastasis.