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(MCRC Non-Clinical) Exploiting the SUMO pathway to target MYC-driven ovarian cancers

Project Description

Project summary:
Ovarian cancer is the fourth commonest cause of cancer in women. The majority of cases are high grade serous ovarian cancer (HGSOC), which typically presents at an advanced stage and develops rapidly. The predominant treatment regimen is cytoreductive surgery and platinum-taxol based chemotherapy and while many patients initially respond most will develop recurrent, chemotherapy-resistant disease. Consequently, ten-year survival rates are only 35%. Therefore, more treatment options are urgently required for this fatal condition.

As the oncogenic transcription factor MYC is frequently amplified in HGSOC and other cancers, we are exploring ways to exploit MYC in the context of ovarian cancer. In particular we are exploring MYC and SUMOylation, a posttranslational modification that regulates various cellular processes. Increased cellular SUMOylation is observed in diverse tumour types and correlates with poor outcome. Strikingly, inhibition of the SUMO E1 activating enzyme SAE1/2 is synthetic lethal with MYC overexpression, suggesting that SUMO-dependent pathways might offer a source of novel drug targets to inhibit MYC-driven ovarian cancers.

This project will evaluate whether SUMO pathways can be exploited to target MYC-driven ovarian cancers. Using a model system in which MYC levels can be controlled, we will confirm the involvement of the canonical SUMOylation pathway and, using an siRNA library screen, we will identify which SUMO E3 ligase is required to tolerate MYC overexpression. Follow up experiments using small molecule inhibitors and proteomic approaches will be employed to define underlying molecular mechanisms. Finally, a living biobank of pre- clinical ovarian cancer models will be screened to identify ex vivo cultures with differential MYC levels. Drug sensitivity profiling will then be used to determine whether MYC influences sensitivity towards SUMO pathway inhibitors. Data from these studies will increase our understanding of the links between MYC and SUMO pathways, and may identify new drug targets.

Entry Requirements:
Candidates must hold, or be about to obtain, a minimum upper second class (or equivalent) undergraduate degree in a relevant subject. A related master’s degree would be an advantage. Applications from all nationalities are welcome.

Funding Notes

The Studentship will cover an annual stipend (currently at £19,000 per annum), running expenses and PhD tuition fees at UK/EU rates. Where international student fees are payable, please provide evidence within your application of how the shortfall will be covered (approximately £19,000 per annum).

The length of this project will be FOUR YEARS.

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