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Title: Evaluation of novel positron emission tomography radiotracers in humans : tissue distribution kinetics and potential for cancer diagnosis and staging
Author: Dubash, Suraiya Rahim
ISNI:       0000 0004 7969 8885
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2019
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Positron emission tomography (PET) imaging has emerged as an important decision-making tool in oncology with respect to diagnosis, staging, and assessment of treatment response. We proposed to investigate the ligand binding and retention kinetics of two novel PET/CT tracers in human tumours that do not normally exhibit high [18F]fluorodeoxyglucose ([18F]FDG) uptake, and a third tracer in the context of specific death mechanism. Biological validation of the imaging endpoint included histological correlation with PET/CT data and establishment of an optimum PET/CT methodologies for the probe for implementation into clinical practice. The internal dosimetry and receptor-mediated tumour localisation of the 'click' labelled [18F]fluoroethyl triazole octreotate analogue, [18F]FET-βAG-TOCA, in neuroendocrine tumours (NETs) were investigated for the first time in humans. The biomarker demonstrated favourable dosimetry, biodistribution and safety. The calculated effective dose over all subjects (mean ± SD) was 0.029 ± 0.004 mSv/MBq. Regarding staging, [18F]FET-βAG-TOCA PET/CT showed high tumoural uptake with high sensitivity (per lesion) compared with [68Ga]DOTATATE PET/CT (92.8% vs 87.5%). Tissue retention kinetics of the novel choline analogue, [18F]fluoromethyl-[1,2-2H4]- choline ([18F]D4-FCH) were investigated in the staging of muscle invasive bladder cancer (MIBC) and non-small cell lung cancer (NSCLC). The biomarker showed high contrast in lung cancer but poor contrast in bladder cancer. In lung tumours, [18F]D4-FCH uptake was quantitatively lower than [18F]FDG. Pharmacokinetic modelling revealed net tracer influx in tumour consistent with radiotracer phosphorylation via choline kinase, however choline kinase-alpha expression did not correlate with PET parameters. Beyond staging, we evaluated for the first time a caspase-3/7 imaging biomarker, [18F](S)- 1-((1-(2-fluoroethyl)-1H-[1,2,3]-triazol-4-yl)methyl)-5-(2(2,4-difluorophenoxymethyl)- 8 pyrrolidine-1-sulfonyl) ([18F]ICMT-11), for imaging apoptosis and/or necrosis in patients; [18F]FDG-PET is not a marker of caspase-3/7 activation. In breast cancer, lung cancer and lymphoma patients receiving first-line chemotherapy treatment, [18F]ICMT-11 and cytokeratin-18 analysis (blood) were performed. [18F]ICMT-11 showed low uptake pre- and post-chemotherapy in all tumours consistent with unremarkable changes in M30/M60 cytokeratin-18 cleavage products in the breast cohort suggesting a lack of predominantly apoptotic cell death mechanism in responding patients. In lung cancer, multi-parametric [18F]ICMT-11 PET/CT, diffusion weighted (DW-MRI) and dynamic contrast enhanced-MRI (DCE-MRI) showed that PET changes were concordant with cell death in the absence of significant perfusion changes. Thus, tumour response could occur in the absence of predominant chemotherapy-induced caspase-3/7 activation measured non-invasively across entire tumour lesions. In conclusion, the optimal clinical context whereby the [18F]ICMT-11 PET endpoint critically determines the outcome of therapy remains to be established.
Supervisor: Aboagye, Eric Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral