A new target to treat ALT-dependent tumours
Primary Supervisor: Professor Peter McHugh
Second Supervisor: Professor Christopher J Schofield
Project Overview
Telomeres are the DNA structures that protect the ends of chromosomes. Cancer cells invariably activate mechanisms required to maintain the length and therefore integrity of these structures as part of their conversion into immortal cells with limitless potential to replicate and metastasise. Most tumours achieve this by upregulating an enzyme called telomerase, but a significant minority of tumours activate a pathway call ‘ALT’ to achieve this aim. Importantly, many tumours that particularly affect children and young people (sarcomas, central nervous system tumours) often rely on the ALT pathway. These tumours have a poor prognosis, and so strategies to target ALT-dependent tumours are badly needed. A recently identified key player in the ALT pathway is the SNM1A DNA repair nuclease. We propose a project to understand the role of SNM1A in ALT, and pioneer methods to inhibit SNM1A as a strategy to selectively target ALT-dependent cancers. In the studentship we will aim to achieve the following: i. Determine whether all ALT-dependent cancer cells reliant on SNM1A for their proliferation? ii. Whether loss of SNM1A associated with the acquisition of hallmarks of telomere damage? If so, this would support a specific role for SNM1A in maintaining telomeres in ALT cancer cells. iii. Determine how SNM1A is recruited to telomeres to during the ALT process? iv. Target SNM1A therapeutically to selectively kill ALT tumour cells? This aim will build upon our established programme of structure guided inhibitor development. Together, this work should provide a definitive answer as to whether SNM1A is an attractive target in ALT-dependent tumours. In the long run, it would allow us to adopt ALT-dependency as an indication for whether SNM1A inhibitors could be utilised. Such targeted therapy could benefit affected young people who currently have few treatment options.
Training Opportunities
The precise training wil depend upon the interests and profile of the student, but will be interdisciplinary in nature, potentially involving: cell culture, genomic engineering (CRISPR-Cas9 and base/prime editing), large-scale screens, general molecular biology methods, DNA damage and repair assays, advanced microscopy, cell sorting methods, protein purification chemical biology, medicinal chemistry, modelling, protein science/enzyme inhibition, and biochemical assays.
References
Gao, J. and Pickett, H.A., 2022. Targeting telomeres: advances in telomere maintenance mechanism-specific cancer therapies. Nature Reviews Cancer, 22(9), pp.515-532.