Ubiquitin signalling in the pathogenesis and therapy of glioblastoma
Nominating Supervisor: Vincenzo D’Angiolella
Second Supervisor: Anderson Ryan
Glioblastoma, the most common primary brain tumor in adults accounts for more than 4000 deaths every year in the UK. The cornerstone of glioblastoma treatment is constituted by maximal surgical resection, radiotherapy and chemotherapy. The therapy has not changed from the 70’ and doctors are in dire need of novel targets and compounds to increase patient survival. Indeed, the prognosis remain dismal with an overall survival of 12-15 months after diagnosis. The D’Angiolella laboratory uses mass spectrometry, CRISPR, biochemistry and cell biology techniques to investigate the role of the Ubiquitin-Proteaome System (UPS) in brain tumor development.
The UPS uses the small molecule ubiquitin to tag proteins in the cells and direct their fate. Given the role of the UPS as a master regulator of protein levels, it has a crucial role in cell survival. The UPS is amenable to specific chemical activation and inhibition, however, the UPS role in glioblastoma development and response to radiotherapy is unknown. The laboratory has performed high resolution CRISPR screens to identify therapeutic vulnerabilities of glioblastoma in combination with radiotherapy. Students will identify the role of novel enzymes as targetable weakness for the treatment of glioblastoma, they will also interact with medicinal chemists to generate novel compounds targeting the UPS like Proteolysis Targeting Chimeras (PROTACs).
Students will be trained in techniques such as high resolution CRISPR screens, biochemical assays and super resolution microscopy. There will be comprehensive training on methods to investigate the ubiquitin system including novel techniques and approaches for PROTACs generation. The laboratory offers the possibility to attend international courses (EMBO and others). Attendance to at least one international conference is guaranteed. Overall students will be in an ideal position to form the scientific basis for their career in cancer research.
D'Angiolella, V. et al. Cyclin F-mediated degradation of ribonucleotide reductase M2 controls genome integrity and DNA repair. Cell 149, 1023-1034, doi:10.1016/j.cell.2012.03.043 (2012).
Raducu, M. et al. SCF (Fbxl17) ubiquitylation of Sufu regulates Hedgehog signaling and medulloblastoma development. The EMBO journal 35, 1400-1416, doi:10.15252/embj.201593374 (2016).
Burdova K. et al., E2F1 proteolysis via SCF-cyclin F underlies synthetic lethality between cyclin F loss and Chk1 inhibition. The EMBO Journal. 2019 Aug 19:e101443. doi: 10.15252/embj.2018101443.