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Radiofluorinated amino acids for oncological positron emission tomography imaging

University of British Columbia

Cancer progression and metastasis are driven by certain molecular features that are either non-existent or abnormally active in normal cells. These features are often exploited by medical scientists for the development of targeted therapies and/or imaging probes to better diagnose and stratify patients. In this thesis, we report the investigation of novel radiotracers designed to measure oxidative stress and the use of amino acids as alternative sources of energy, both associated with malignant transformation and resulting in upregulation of different amino acid transporters (AATs). Oxidative stress has been implicated as a feature of aggressive cancer types, particularly those with poor prognosis. System xC- is an antiporter of cystine and glutamate, which is upregulated under oxidative stress and overexpressed in many cancers including triple-negative breast cancer and glioblastoma. System xC- provides cells with a substrate for antioxidant synthesis. This transporter can be studied by positron emission tomography (PET) using ¹⁸F-fluoroaminosuberic acid ([¹⁸F]FASu). [¹⁸F]FASu is hypothesized to be a specific substrate for system xC- activity. The work herein explores the relationship between [¹⁸F]FASu uptake and system xC- transporter activity, and whether this can be used for cancer diagnosis and treatment response monitoring. We studied system xC- activity and overexpression in vitro and used [¹⁸F]FASu in vivo to monitor intratumoural changes following radiotherapy. We evaluated a novel [¹⁸F]FASu analogue, [¹⁸F]ASu-BF3, synthesized via an alternative radiolabelling method. Additionally, we compared [¹⁸F]FASu to two other PET radiopharmaceuticals in vivo, one of which also targets system xC-. Finally, this thesis also explores a novel radiolabelling methodology and biological characterisation of a number of radiofluorinated leucine derivatives, substrates for another AAT, LAT1. LAT1 is highly upregulated in several cancers and at metastatic sites. LAT1 is a poor prognostic biomarker in cancer patients. It is associated with mTOR pathway activation, through which amino acids are being imported and used as substrates for protein biosynthesis. This research presents effective methodology for producing LAT1 substrates for the purposes of cancer imaging with PET. Collectively, this research provides a non-invasive platform for the characterization of two AAT proteins, both of which play a role in cancer development and progression.

Text

2022-01-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/73222

Interdisciplinary Oncology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/