HIGGINS GROUP

RESEARCH SUMMARY

I am a Clinician Scientist in Clinical Oncology undertaking both laboratory and clinical research. I run a research laboratory focused on improving the efficacy of radiotherapy by developing treatments that specifically make tumour cells more sensitive to radiotherapy. The ultimate aim of this work is to develop treatments to improve the ability of radiotherapy to cure patients without increasing side-effects.

Our work often involves developing new drug treatments in combination with either commercial partners or academic collaborators within the University of Oxford.

In the clinic, I treat lung cancer patients with radiotherapy, chemotherapy and immunotherapy. I lead clinical trials that translate our most promising laboratory findings into patient studies.

I have significant experience in undertaking clinical trials relevant to radiotherapy and am the Director of the CRUK Oxford RadNet centre. My clinical trials typically incorporate novel functional imaging of the tumour microenvironment (e.g. perfusion CT, OE-MRI & hypoxia PET-CT) and I am joint-lead investigator of the “National Cancer Imaging Translational Accelerator” (NCITA) award from CRUK.

IMPACT

We have previously identified therapeutic targets which modulate “intrinsic” radiosensitivity by altering processes such as DNA damage repair (eg DNA Polymerase Theta), or intracellular signalling (eg TOPK). This has led to the development of large-scale drug development programmes which have successfully been adopted by commercial collaborators such as Artios Pharma.
In addition, we have also identified treatments that effectively alter the tumour microenvironment. For example, we have previously found that the safe and widely used antimalarial drug atovaquone inhibits oxidative phosphorylation, reducing hypoxia, and leading to tumour radiosensitisation.

I am currently the Chief Investigator for two clinical trials:

• The ARCADIAN trial (Atovaquone with Radical ChemorADIotherapy in locally Advanced NSCLC) follows on from our laboratory work identifying atovaquone as a novel radiation sensitiser and leads on directly from our previous proof of concept trial (ATOM) demonstrating the ability of this drug to reduce tumour hypoxia in lung cancers.

• The FIG trial (18F-FDOPA PET imaging in GLIOMA: feasibility study for PET guided brain biopsy) is investigating the benefit of using an amino acid PET tracer to more accurately identify low and high grade gliomas (https://ncita.org.uk/exemplar-7).

• Rodriguez-Berriguete, G., Puliyadi, R., Machado, N., Barberis, A., Prevo, R., McLaughlin, M., Buffa, F.M., Harrington, K.J. and Higgins, G.S., 2024. Antitumour effect of the mitochondrial complex III inhibitor Atovaquone in combination with anti-PD-L1 therapy in mouse cancer models. Cell Death & Disease, 15(1), pp.1-10.
• Rodriguez-Berriguete, G., Ranzani, M., Prevo, R., Puliyadi, R., Machado, N., Bolland, H.R., Millar, V., Ebner, D., Boursier, M., Cerutti, A. and Cicconi, A., 2023. Small-molecule Polθ inhibitors provide safe and effective tumor radiosensitization in preclinical models. Clinical Cancer Research, 29(8), pp.1631-1642.
• Belan, O., Sebald, M., Adamowicz, M., Anand, R., Vancevska, A., Neves, J., Grinkevich, V., Hewitt, G., Segura-Bayona, S., Bellelli, R. and Robinson, H.M., 2022. POLQ seals post-replicative ssDNA gaps to maintain genome stability in BRCA-deficient cancer cells. Molecular cell, 82(24), pp.4664-4680.
• Zatreanu, D., Robinson, H.M., Alkhatib, O., Boursier, M., Finch, H., Geo, L., Grande, D., Grinkevich, V., Heald, R.A., Langdon, S. and Majithiya, J., 2021. Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance. Nature communications, 12(1), p.3636.
• Skwarski, M., McGowan, D.R., Belcher, E., Di Chiara, F., Stavroulias, D., McCole, M., Derham, J.L., Chu, K.Y., Teoh, E., Chauhan, J. and O’Reilly, D., 2021. Mitochondrial inhibitor atovaquone increases tumor oxygenation and inhibits hypoxic gene expression in patients with non–small cell lung cancer. Clinical Cancer Research, 27(9), pp.2459-2469.
• Herbert, K.J., Puliyadi, R., Prevo, R., Rodriguez-Berriguete, G., Ryan, A., Ramadan, K. and Higgins, G.S., 2021. Targeting TOPK sensitises tumour cells to radiation-induced damage by enhancing replication stress. Cell Death & Differentiation, 28(4), pp.1333-1346.
• Ruggiano, A., Vaz, B., Kilgas, S., Popović, M., Rodriguez-Berriguete, G., Singh, A.N., Higgins, G.S., Kiltie, A.E. and Ramadan, K., 2021. The protease SPRTN and SUMOylation coordinate DNA-protein crosslink repair to prevent genome instability. Cell Reports, 37(10).