Journal
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
Volume 45, Issue 13, Pages 2285-2299Publisher
SPRINGER
DOI: 10.1007/s00259-018-4098-9
Keywords
Apoptosis; Positron emission tomography; [F-18]ICMT-11; Isatin sulfonamide; Caspase-3
Funding
- U.K. Medical Research Council (MRC) [MC-A652-5PY80]
- European Commission Innovative Medicines Initiative QuIC-ConCePT consortium [115,151]
- Joint Cancer Research U.K.
- Engineering and Physical Sciences Research Council Cancer Imaging Centre at Imperial College London
- MRC
- Department of Health (England) [C2536/A10337]
- Experimental Cancer Medicine Centres grant [C37/A7283]
- National Institute for Health Research (NIHR) Biomedical Research Centre
- NIHR Clinician Scientist Award [09/009]
- MRC [MC_U120081322, MR/N020782/1] Funding Source: UKRI
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BackgroundEffective anticancer therapy is thought to involve induction of tumour cell death through apoptosis and/or necrosis. [F-18]ICMT-11, an isatin sulfonamide caspase-3/7-specific radiotracer, has been developed for PET imaging and shown to have favourable dosimetry, safety, and biodistribution. We report the translation of [F-18]ICMT-11 PET to measure chemotherapy-induced caspase-3/7 activation in breast and lung cancer patients receiving first-line therapy.ResultsBreast tumour SUVmax of [F-18]ICMT-11 was low at baseline and unchanged following therapy. Measurement of M30/M60 cytokeratin-18 cleavage products showed that therapy was predominantly not apoptosis in nature. While increases in caspase-3 staining on breast histology were seen, post-treatment caspase-3 positivity values were only approximately 1%; this low level of caspase-3 could have limited sensitive detection by [F-18]ICMT-11-PET. Fourteen out of 15 breast cancer patients responded to first-line chemotherapy (complete or partial response); one patient had stable disease. Four patients showed increases in regions of high tumour [F-18]ICMT-11 intensity on voxel-wise analysis of tumour data (classed as PADS); response was not exclusive to patients with this phenotype. In patients with lung cancer, multi-parametric [F-18]ICMT-11 PET and MRI (diffusion-weighted- and dynamic contrast enhanced-MRI) showed that PET changes were concordant with cell death in the absence of significant perfusion changes.ConclusionThis study highlights the potential use of [F-18]ICMT-11 PET as a promising candidate for non-invasive imaging of caspase3/7 activation, and the difficulties encountered in assessing early-treatment responses. We summarize that tumour response could occur in the absence of predominant chemotherapy-induced caspase-3/7 activation measured non-invasively across entire tumour lesions in patients with breast and lung cancer.
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