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Title: Cancer imaging with fluciclovine (18F)
Author: Teoh, Eugene
ISNI:       0000 0004 7430 7478
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2018
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[18F]1-amino-3-fluorocyclobutane 1-carboxylic acid (18F-fluciclovine) is a synthetic amino acid developed as a PET radiotracer for cancer imaging. Upon project commencement, 18F-fluciclovine was in late phase of pharmaceutical development for recurrent prostate cancer imaging, requiring validation of clinical utility. Growing prospect in targeting of tumour metabolism in breast cancer treatment set the premise to investigate the role of amino acid imaging in this prevalent disease. The aims of this project were to: (1) establish the transport mechanisms of fluciclovine in breast cancer; (2) explore the utility of fluciclovine in early assessment of response to treatments of related metabolic and biological targets; (3) run a clinical study to investigate how 18F-fluciclovine uptake can be used to characterise breast cancer biology; and (4) run a multicentre clinical trial to investigate the impact of 18F-fluciclovine imaging on clinical management of men with recurrent prostate cancer. Fluciclovine transport in breast cancer was found to be predominantly mediated by the high-affinity glutamine transporter ASCT2. Increased fluciclovine uptake was demonstrated in cell lines sensitive to glutaminase inhibition with CB-839 (known to result in build-up of intra-cellular glutamine); and the opposite with bithionol and metformin which are known to reduce intra-cellular glutamine. These results were recapitulated in animal models, and collectively raise the potential for fluciclovine to be used as an imaging biomarker of glutamine pool, in addition to early response assessment in therapies augmenting glutamine metabolism. The FRONTIER study was established to investigate how 18F-fluciclovine can be used to characterise breast cancer biology and is ongoing. Initial data demonstrate a trend of highest uptake in triple-receptor negative, followed by ER+ then HER2+ tumours, complementing in vitro data. The FALCON multicentre trial investigated the impact of 18F-fluciclovine imaging on clinical management of recurrent prostate cancer. In the 32-patient Oxford cohort, 44% of patients had their intended management plan revised following 18F-fluciclovine PET/CT. Initial short term follow-up data demonstrate a higher proportion of short-term responders to 18F-fluciclovine guided radiotherapy (71%, 5/7) compared to standard radiotherapy (53%, 8/15). This encouraging trend will require ratification with trial-wide data. Across the trial, interim analysis found management was revised post-scan in 52/85 (61%) patients, exceeding a pre- set criteria for overwhelming effectiveness (45/85), leading to early closure.
Supervisor: Gleeson, Fergus ; Harris, Adrian Sponsor: Cancer Research UK
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available