Imaging L-Carnitine Utilisation In Non-Small Cell Lung Cancer

Metabolic reprogramming in tumours is a key hallmark of malignancy, allowing for rapid proliferation and growth. Tumours upregulate glycolytic flux in the phenomenon known as the 'Warburg effect', which is accompanied by increased beta-oxidation and glutaminolysis. beta-oxidation supports adenosine triphosphate (ATP) production and synthesis of proteins, lipids, and nucleotides required for growth, invasion, and metastasis. L-Carnitine (LC) plays a key role in beta-oxidation, allowing for transport of fats into the mitochrondria, and has been shown to protect tumours from oxidative and metabolic stress and thus contribute to drug resistance. LC is transported into the cells by the Na+-dependent novel organic cation transporter-2 (OCTN2). OCTN2 expression has been associated with poor patient survival in glioma. OCTN/LC inhibition has been shown to reduce glioma cell proliferation and diminished in vivo tumour growth in an orthotopic GBM mouse model. However, the levels of OCTN2 expression and its role in lung cancer have yet to be assessed. Hence, LC and its transporter OCTN2 offer a novel opportunity for investigation into tumour metabolism and drug resistance in lung cancer. Through Fluorine-18 [18F] labelling of LC, Positron emission tomography (PET) imaging presents the opportunity to understand LC transport and uptake through OCTN2, their expression in lung cancer and LC-induced tumour survival, proliferation, and therapy resistance. This project aims to understand LC utilisation and metabolism in lung cancer. The affinity and specificity of fluorinated LC for OCTN2 imaging using OCTN2 wild-type, knockdown (siRNA) and knockout (CRISPR-Cas9) will be assessed. The [18F] LC tracer pharmacokinetics, tumour uptake and radiotracer stability in mice will then be assessed. The potential of [18F] LC to measure target engagement following treatments with chemotherapy and in models of inflammation will then be assessed.