Are Rab GTPases therapeutic targets in paediatric brain tumours?

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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.