Targeting polymerase theta as a way to improve radiotherapy and immunotherapy.
About the research:
Despite technical improvements in radiation delivery, survival rates following radical radiotherapy remain poor for many tumour types and the radiation delivered to adjacent tissues is still frequently associated with significant side-effects. The aim of our research is to improve radiotherapy for cancer patients by making tumour cells more sensitive to radiation without affecting the sensitivity of normal cells.
We have previously identified that depletion of DNA polymerase theta (POLQ) makes tumour cells more sensitive to radiation. POLQ is a DNA repair polymerase that plays a role in micro-homology mediated end-joining (MMEJ), an alternative DNA double-strand break repair pathway. POLQ is frequently overexpressed in many cancer types and this has been shown to be associated with adverse clinical outcomes. Importantly, POLQ has low or absent expression in most normal tissues and therefore represents an ideal tumour-specific radiosensitisation target. We established a drug development programme to make inhibitors against POLQ, which was subsequently spun-out into a new company (Artios). Through our collaboration with Artios, we now have unique access to potent and first-in-class POLQ inhibitors, which we have shown to radiosensitise tumour cells but not normal cells.
This project aims to explore the most effective ways in which POLQ inhibitors can be applied clinically as a radiosensitising agent. The project will also investigate whether POLQ inhibitors can improve the efficacy of immune checkpoint inhibitors, a new treatment modality that is often combined with (chemo) radiotherapy. While clinical trials with immunotherapy have shown promising results, many patients do not respond or do not have durable responses. We have seen that POLQ inhibition in combination with radiation can increase cGAS-STING pathway activity, a key activator of immune stimulatory signalling. Based on this we believe that the increased radiosensitivity seen with POLQ inhibition can translate into increased efficacy of immune checkpoint – radiotherapy combination.
Having hosted nine DPhil students over the last ten years, our group has an excellent track record in supervising DPhil candidates. Aside from supervision from the principal investigator, the successful candidate will be thoroughly trained and closely mentored by experienced post-doctoral scientists in the group. Our group is very experienced in molecular biological and tissue culture techniques, high-throughput screening, epifluorescence and confocal microscopy, including high content and live cell imaging, and flow cytometry. We complement laboratory studies with in vivo experiments using state-of-the-art pre-clinical radiation and imaging techniques and have set up two clinical trials based on findings in our lab. This project offers a unique opportunity to be at the forefront of drug development and to gain a wide range of experimental and transferable skills.
Our close collaboration with Artios offers the candidate exposure to clinical drug development and the potential to spend some time in the company’s laboratories.
Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance.
Nat Commun. 2021 3636. doi: 10.1038/s41467-021-23463-8. PMID: 34140467
Zatreanu D, Robinson HMR, Alkhatib O, Boursier M, Finch H, Geo L, Grande D, Grinkevich V, Heald RA, Langdon S, Majithiya J, McWhirter C, Martin NMB, Moore S, Neves J, Rajendra E, Ranzani M, Schaedler T, Stockley M, Wiggins K, Brough R, Sridhar S, Gulati A, Shao N, Badder LM, Novo D, Knight EG, Marlow R, Haider S, Callen E, Hewitt G, Schimmel J, Prevo R, Alli C, Ferdinand A, Bell C, Blencowe P, Bot C, Calder M, Charles M, Curry J, Ekwuru T, Ewings K, Krajewski W, MacDonald E, McCarron H, Pang L, Pedder C, Rigoreau L, Swarbrick M, Wheatley E, Willis S, Wong AC, Nussenzweig A, Tijsterman M, Tutt A, Boulton SJ, Higgins GS, Pettitt SJ, Smith GCM, Lord CJ.
Beyond PARP-POLθ as an anticancer target. Science. 2018, 359:1217-1218. doi: 10.1126/science.aar5149. Higgins GS, Boulton SJ