Our research focuses on finding new ways of making tumours more sensitive to radiotherapy treatment.
Although radiotherapy is effective at curing many different types of cancer, some tumours are recognised as being resistant to radiation treatment.
The presence of genetic and epigenetic changes in tumour cells can lead to ‘intrinsic radioresistance’, whilst the presence of an abnormal tumour microenvironment such as tumour hypoxia can lead to ‘extrinsic radioresistance’
Our laboratory research has involved large-scale drug and siRNA screens to find new ways of increasing tumour radiosensitivity. Our aim is to use these findings to develop treatments that can be combined with radiotherapy to improve outcomes for cancer patients. For example, we previously identified that depletion of DNA polymerase theta (POLQ) induces tumour specific radiosensitisation. We subsequently established a collaboration with Cancer Research Technology to develop inhibitors against this target. This work has subsequently been spun-out into a new company (Artios) which has POLQ as its lead programme. We continue to work closely with Artios in the development of these compounds.
We aim to translate our laboratory findings into clinical trials and I am currently the Chief Investigator of two such studies. My clinical work has a strong focus on lung cancer as radiotherapy plays a key role in the management of this disease yet is still associated with poor outcomes.
Our trials often involve the use of functional imaging, such as perfusion CT scans and 18F-Misonidazole PET-CT scans, to detect changes in tumour blood flow and regions of tumour hypoxia, respectively. By performing these scans before and after drug treatment we can assess whether hypoxia has been reduced in the tumour, making it more likely to respond favourably to radiotherapy.
Figure legend: 18F-Misonidazole PET-CT scan showing a large left upper lobe tumour with lymph node metastases. Hypoxic areas of the tumour are represented by red regions on the scan.
Geoff Higgins is an Associate Professor in the CRUK/MRC Oxford Institute for Radiation Oncology, having held a Cancer Research UK Clinician Scientist award since 2011. He is an Honorary Consultant Clinical Oncologist in Oxford University Hospitals NHS Trust and is a Medical Research Fellow at Corpus Christi College. He previously undertook specialist medical training at the Edinburgh Cancer Centre before moving to Oxford as a Cancer Research UK Clinical Research Fellow in 2007.
Nucleoporin 54 contributes to Homologous Recombination repair and post-replicative DNA integrity. Rodriguez-Berriguete G, Granata G, Puliyadi R, Tiwana G, Prevo R, Yu S, Buffa F, Humphrey TC, McKenna WG, Higgins GS. Nucleic Acids Res. Jul 9: 2018.
Beyond PARP - POLq as an anticancer target. Higgins GS, Boulton SJ. Science. 2018. Mar 16: 1217-1218.
Non-Parametric 4D-PET Reconstruction using a Spline Residue Model with Spatial and Temporal Roughness Penalties. Ralli GP, Chappell MA, McGowan DR, Sharma RA, Higgins GS*, Fenwick JD*. (*Equal contribution) Phys Med Biol. 2018 Apr 4. doi: 10.1088/1361-6560/aabb62.
Oxidative phosphorylation as an emerging target in cancer therapy. Ashton T, McKenna WG, Kunz-Schughart LA, Higgins GS. Clin Cancer Res. 2018 Feb 2. pii: clincanres.3070.2017
Targeting tumour hypoxia: shifting focus from oxygen supply to demand. Coates J, Skwarski M, Higgins GS. Br J Radiol. 2018 Feb 19:20170843. doi: 10.1259/bjr.20170843.
The Future of Radiobiology. Kirsch DG, et al. J Natl Cancer Inst. 2017 Nov 3. doi: 10.1093/jnci/djx231.
Depletion of Signal Recognition Particle 72kDa increases radiosensitivity. Prevo R, Tiwana GS, Maughan TS, Buffa FM, McKenna WG, Higgins GS. Cancer Biol Ther. 2017 Jun 3;18(6):425-432
TOPK modulates tumour-specific radiosensitivity and correlates with recurrence after prostate radiotherapy. Pirovano G, Ashton T, Herbert K, Bryant R, Verrill C, Cerundolo L, Buffa F, Prevo R, Harrap I, Ryan A, Macauley V, McKenna WG, Higgins GS. 2017 Br J Cancer Aug 8;117(4):503-512
18F-fluoromisonidazole uptake in advanced stage non-small cell lung cancer: A voxel-by-voxel PET kinetics study. McGowan D, Macpherson RE, Hackett SL, Liu D, Gleeson FV, McKenna WG, Fenwick JD*, Higgins GS*. (*Equal contribution) 2017 Med Phys 44(9):4665-4676.
A new roadmap to improve translation of imaging biomarkers. Skwarski M, Higgins GS. 2016 BJC Dec 6;115(12):1443-1444.
Dose and fractionation in radiotherapy of curative intent for non-small-cell lung cancer: Meta-analysis of randomized trials. Rankin JC et al. 2016 Int J Rad Oncol Biol Phys. Nov 15;96(4):736-747
Improving the Predictive Value of Preclinical Studies in Support of Radiotherapy Clinical Trials. Coleman NC et al. 2016. Clin Cancer Res. Jul 1;22(13):3138-47
The anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia. Ashton TM, Fokas E, Kunz-Schughart LA, Folkes LK, Anbalagan S, Huether M, Kelly CJ, Pirovano G, Buffa FM, Hammond EM, Stratford M, Muschel RJ, McKenna WG*, Higgins GS*. (Equal contribution) 2016 Nat. Commun. Jul 25;7:12308
Drug Radiotherapy Combinations: Review of previous failures and reasons for future optimism. Higgins GS, O’Caithail S, Muschel RJ, McKenna WG. Cancer Treat Rev. 2015 Feb; 41(2):105-113
Overexpression Of POLQ Confers a Poor Prognosis In Early Breast Cancer Patients. Higgins GS, Harris AL, Prevo R, Helleday T, McKenna WG, Buffa FM. Oncotarget. 2010 ; 1(3):175-184
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; 70 :2984-93.