Developing novel radiotracers for positron emission tomography: probing different cancer phenotypes and therapy response in living subjects


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Eric O Aboagye1
1Imperial College London, London, UK

Abstract

Tumour cells exhibit several properties including deranged cell surface receptor expression and intracellular signalling that, together with their microenvironment, allow them to grow and divide. Radiotracers can be designed to detect and quantify several of these tumour cell-specific and aberrant microenvironment properties. The lecture will initially provide an overview of crucial tumour properties that can be described by current radio-probe technologies for imaging by positron emission tomography (PET) including DNA synthesis, apoptosis, extracellular/transmembrane receptor signalling, and intracellular signalling. The strategies for imaging cell surface receptors and intracellular effectors are distinct, thus, chemistry design exploits different molecular scaffolds including small molecules, peptides, affibodies and antibodies. Specific examples of such imaging strategies will be given to highlight: a) reporting of cell surface receptors with a view to stratifying patients for therapy; and b) imaging of intracellular caspase 3 cleavage for detection of therapy response.  A ZHER2:2891 affibody labelled with fluorine-18 radioisotope can be used to detect HER2 expression in cells and xenografts independent of lineage. We show that tumour uptake correlates with HER2 expression determined by ELISA and reflects HER2 degradation by short-term with the HSP90 inhibitor NVP-AUY922. Regarding apoptosis, we discovered the cleaved-caspase 3/7 binder 18F-ICMT-11. This tracer shows specific binding to cells undergoing apoptosis, which exhibit increased activation of caspase 3/7.  The optimal timing of apoptosis remains a challenge and differs between molecularly targeted drugs and chemotherapy. Lastly, voxel analysis of PET data is an evolving research area and aims to provide added information on functional tissue heterogeneity in the entire disease volume in patients.