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Identifying and developing clinically exploitable treatments to widen the therapeutic window of 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.
Coronal image of a clinical trial patient imaged with 18F-fluoromisonidazole PET/CT. Image shows a hypoxic primary tumour in addition to several hypoxic nodes. Displayed on a tumour to blood ratio (TBR) colour scale. Red regions depict a TBR > 1.4 indicating hypoxia, and no visible PET depicts a TBR < 1, indicating normoxia

Summary:

The Higgins group is focused on identifying and developing clinically exploitable treatments to widen the therapeutic window of radiotherapy. Where possible, he translates these laboratory findings into scientifically driven clinical trials which often utilise serial tumour sampling and state of the art functional imaging to demonstrate pharmacodynamic efficacy.  

His laboratory research has previously identified several genetic and pharmacological determinants of radiotherapy which have successfully progressed to clinical trials.  

He previously found that depletion of DNA Polymerase Theta (POLQ), a key protein involved in microhomology mediated end joining (MMEJ) repair renders tumour cells significantly more sensitive to radiotherapy (1), and that tumours with high POLQ expression are associated with worse clinical outcomes following radiotherapy treatment (2). Since POLQ has extremely restricted normal tissue expression but is overexpressed in a wide range of different tumours, he hypothesised that pharmacological inhibition of POLQ would represent an ideal radiosensitisation strategy since it would be expected to improve tumour control without exacerbating normal tissue toxicity (3). He therefore initiated a drug development programme against POLQ in collaboration with Cancer Research Technology (CRT). This work proved highly successful and was spun out to form a new company (Artios Pharma Ltd) in 2016. Geoff has continued to collaborate closely with Artios in the development of these compounds including developing the pre-clinical data required to initiate clinical trials of POLQ inhibitors plus radiotherapy.

The Higgins group is also interested in identifying methods to alleviate tumour hypoxia, a key determinant of resistance to radiotherapy treatment, by targeting the oxygen consumption rate (OCR) of tumour cells. Through a high throughput screen of an FDA-approved drug library for novel OCR-reducing compounds, he identified that the anti-malarial drug atovaquone inhibits oxygen consumption in cancer cells, and alleviates tumour hypoxia in mouse models leading to tumour radiosensitisation (4). Geoff successfully secured external funding to test these findings in a phase I clinical trial (“ATOM”) in non-small cell lung cancer (NSCLC) patients. His trial showed that atovaquone significantly reduced tumour hypoxia in these patients, providing the first clinical evidence that targeting tumour mitochondrial metabolism can reduce hypoxia (5). He has now obtained CRUK funding to take these findings into a new trial (ARCADIAN), which will investigate the safety and efficacy of combining atovaquone with chemo-radiotherapy in NSCLC patients. 

Geoff’s expertise in functional imaging and his links with clinicians across the country enabled him to help establish the National Cancer Imaging Translational Accelerator (NCITA) consortium, for which he is joint-lead investigator. This nationwide imaging network seeks to establish imaging trial infrastructure for the UK and was awarded a £10M grant from CRUK.  

The Higgins group has received funding through several industrial partnerships, including collaborations with companies specialising in tumour immunology, theragnostics and DNA damage repair. In addition, he is collaborating with GenesisCare for his ‘FIG’ trial, testing the use of a novel amino acid PET tracer to more effectively stratify those glioma patients that require radiotherapy. He was also a co-applicant on a recent successful bid to the Rising Tide Foundation to secure funding to take a mitochondrial inhibitor developed by an industrial collaborator (Novintum) into single agent and combinatorial pre-clinical studies.   

The Higgins group have significant experience in using in vitro and in vivo tumour and normal tissue models to validate the clinical potential of new radiosensitising strategies and his expertise is highly sought after in the unit. As his interests lie in both DNA repair mechanisms and the tumour microenvironment, Geoff has worked closely with other past and current principal investigators in the unit. This included sharing his expertise and tools to undertake and analyse high throughput screens (D’Angiolella), co-supervision of MSc and DPhil students (Hammond, Petersson) and collaboration on in vivo experimentation (Petersson). Together these collaborations have resulted in co-authorships with many PIs in the unit, including Tim Humphrey (6,7), Ester Hammond (4,8,9), Kristoffer Petersson (9) and Kristijan Ramadan (10,11).  

Impact:

Geoff is the only radiation oncology group leader leading both laboratory and clinical research in the unit and is central to OIRO’s ability to translate scientific findings to the clinic. He has previously translated not just his own, but also other people’s laboratory findings into clinical trials. His clinical practice and research studies routinely involve the use of ‘advanced’ radiotherapy and imaging techniques such as SABR and dynamic PET scanning and oxygen-enhanced MRI, which enables him to create a credible bridge between laboratory scientists and practicing oncologists, radiotherapy physicists, and radiologists.

References:

1. Higgins GS, Prevo R, Lee YF, Helleday T, Muschel RJ, Taylor S, Yoshimura M, Hickson ID, Bernhard EJ & McKenna WG. (2010) A small interfering RNA screen of genes involved in DNA repair identifies tumor-specific radiosensitization by POLQ knockdown. Cancer Res 70, 2984-93. 


2. Higgins GS, Harris AL, Prevo R, Helleday T, McKenna WG & Buffa FM. (2010) Overexpression of POLQ confers a poor prognosis in early breast cancer patients. Oncotarget 1, 175-84. 


3. Higgins GS & Boulton SJ. (2018) Beyond PARP-POLtheta as an anticancer target. Science 359, 1217-18. 


4. 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, Higgins GS & McKenna WG. (2016) The anti-malarial atovaquone increases radiosensitivity by alleviating tumour hypoxia. Nat Commun 7, 12308. 


5. Skwarski M, McGowan DR, Belcher E, Di Chiara F, Stavroulias D, McCole M, Derham JL, Chu KY, Teoh E, Chauhan J, O'Reilly D, Harris BHL, Macklin PS, Bull JA, Green M, Rodriguez-Berriguete G, Prevo R, Folkes LK, Campo L, Ferencz P, Croal PL, Flight H, Qi C, Holmes J, O'Connor JPB, Gleeson FV, McKenna WG, Harris AL, Bulte D, Buffa FM, Macpherson RE & Higgins GS. (2021) Mitochondrial Inhibitor Atovaquone Increases Tumor Oxygenation and Inhibits Hypoxic Gene Expression in Patients with Non-Small Cell Lung Cancer. Clin Cancer Res. 


6. Ahrabi S, Sarkar S, Pfister SX, Pirovano G, Higgins GS, Porter AC & Humphrey TC. (2016) A role for human homologous recombination factors in suppressing microhomology-mediated end joining. Nucleic Acids Res 44, 5743-57. 


7. Rodriguez-Berriguete G, Granata G, Puliyadi R, Tiwana G, Prevo R, Wilson RS, Yu S, Buffa F, Humphrey TC, McKenna WG & Higgins GS. (2018) Nucleoporin 54 contributes to homologous recombination repair and post-replicative DNA integrity. Nucleic Acids Res 46, 7731-46. 


8. Sayal KK, Higgins GS & Hammond EM. (2016) Uncovering the influence of the FGFR1 pathway on glioblastoma radiosensitivity. Ann Transl Med 4, 538. 


9. Wilson JD, Hammond EM, Higgins GS & Petersson K. (2019) Ultra-High Dose Rate (FLASH) Radiotherapy: Silver Bullet or Fool's Gold? Front Oncol 9, 1563. 


10. Herbert KJ, Puliyadi R, Prevo R, Rodriguez-Berriguete G, Ryan A, Ramadan K & Higgins GS. (2021) Targeting TOPK sensitises tumour cells to radiation-induced damage by enhancing replication stress. Cell Death Differ 28, 1333-46. 


11. Vaz B, Ruggiano A, Popovic M, Rodriguez-Berriguete G, Kilgas S, Singh AN, Higgins GS, Kiltie AE & Ramadan K. (2020) SPRTN protease and SUMOylation coordinate DNA-protein crosslink repair to prevent genome instability. bioRxiv, 2020.02.14.949289.