Pre-clinical investigations of POLQ inhibitors
Nominating Supervisor: Geoff Higgins
Second Supervisor: Tim Humphrey
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. This would achieve greater tumour control without exacerbating side effects from damage to the adjacent tissues.
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).
In collaboration with Artios, we are testing specific POLQ inhibitors and have shown that they radiosensitise tumour cells but not normal cells. Through POLQ inhibition, tumour cells are less able to repair their radiation-induced DNA double strand breaks and thus more likely to die after radiotherapy.
This project aims to explore the most effective ways in which POLQ inhibitors can be applied clinically as a radiosensitising agent, exploring separate clinically relevant aspects. This will include exploring development of resistance to POLQ inhibition and assess the effect of POLQ inhibitors in hypoxia, a common feature of solid tumours that imparts resistance to radiotherapy. We also hypothesise that POLQ inhibition in combination with radiation will increase cGAS-STING pathway activity, a key activator of immune stimulatory signalling. The project will therefore also investigate whether POLQ inhibitors can improve the efficacy of immune checkpoint inhibitors, an effective cancer treatment, but which still requires optimisation to benefit a larger proportion of patients.
Having hosted seven DPhil students over the last nine 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 will offer the candidate exposure to clinical drug development and the potential to spend some time in Artios’s laboratories.
Beyond PARP-POLθ as an anticancer target. Science. 2018 Mar 16;359(6381):1217-1218. doi: 10.1126/science.aar5149. Higgins GS, Boulton SJ, Science. 2018 Mar 16;359(6381):1217-1218
A role for human homologous recombination factors in suppressing microhomology-mediated end joining. Ahrabi S, Sarkar S, Pfister SX, Pirovano G, Higgins GS, Porter AC, Humphrey TC. Nucleic Acids Res. 2016 Jul 8;44(12):5743-57.
A small interfering RNA screen of genes involved in DNA repair identifies tumor-specific radiosensitization by POLQ knockdown. Higgins GS, Prevo R, Lee YF, Helleday T, Muschel RJ, Taylor S, Yoshimura M, Hickson ID, Bernhard EJ, McKenna WG. Cancer Res. 2010 Apr 1;70(7):2984-93