Cell Death

Patients with similar tumour types can show markedly different responses to the same therapy, reflecting substantial tumour heterogeneity underpinning inherent and acquired drug resistance. The development of new treatments would benefit, therefore, from the introduction of imaging methods that allow an early assessment of treatment response in individual patients, allowing rapid selection of the most effective treatment for a specific patient. One such approach is the detection of cell death, as levels of cell death early following treatment can be a good predictor of treatment outcome.

 

 

Cambridge has been developing a targeted imaging agent for detecting tumour cell death, based on the C2A domain of the protein synaptotagmin I, which binds to the phosphatidylserine (PS) that is exposed by dying cells. Initially this molecule was labelled with agents that could be detected using magnetic resonance imaging (MRI), but more recently we have focused on labelling the protein with radioactive metals for radionuclide imaging and with fluorescent dyes for near-infra-red imaging. We have produced a mutant of C2A (C2Am), for which a patent application has been filed, and using this we have demonstrated that we can detect cell death in a drug-treated tumour using single photon emission computed tomography (SPECT). Initial studies with fluorescently labelled C2A-mutant derivatives have shown that this mutant has better specificity for detecting cell death than Annexin V, an agent that had showed promise but has since raised concerns regarding suboptimal pharmacokinetics with non-specific binding.

We will develop a new approach for the rapid labelling of C2Am with positron emission tomography (PET) and SPECT isotopes using copper-free click chemistry, with which we already have extensive experience. We will explore the use of labeled C2Am in vitro and also in vivo in lymphoma models. 

We will also evaluate these agents in a novel ‘death switch’ model, developed in Manchester, in which doxycycline induces apoptosis in human or mouse xenografts. This model has already been used for both MRI and PET imaging studies in Manchester to evaluate existing putative biomarkers of cell death and apoptosis.

Detection of tumour cell death using radiolabelled C2Am derivatives in the lymphoma and ‘death-switch’ models will be evaluated in comparison with the diffusion weighted MRI techniques and the hyperpolarised 13C-labelled glucose measurements for detecting tumour cell death. These imaging methods will also be evaluated in comparison with serum-based assays for detecting tumour cell death, including appearance of tumour cell death products in the circulation and circulating tumour cell and tumour DNA methods.

 

Professor Kevin Brindle

Chair in

Biomedical Magnetic Resonance at the University of Cambridge.



Dr Finian Leeper

Senior Lecturer at the University of Cambridge.

Professor Geoff Parker

Chair in Biomedical Imaging at The University of Manchester.

 

Dr Dmitry Solviev

Senior Staff Scientist at Cancer Research UK Cambridge Institute.

  

Professor Kaye Williams

Head of the Hypoxia and Therapeutics group in the Manchester Pharmacy School at The University of Manchester.