Evaluation of apoptosis imaging biomarkers in a genetic model of cell death
Simpson, Kathryn L
Illidge, Timothy M
AffiliationHospital for Children and Adolescents; Division for Stem Cell Transplantation and Immunology, University Hospital Frankfurt, Frankfurt, Germany
MetadataShow full item record
AbstractPURPOSE: We have previously developed the caspase-based radiotracer, 18F-ICMT-11, for PET imaging to monitor treatment response. We further validated 18F-ICMT-11 specificity in a murine melanoma death-switch tumour model with conditional activation of caspase-3 induced by doxycycline. METHODS: Caspase-3/7 activity and cellular uptake of 18F-ICMT-11, 18F-ML-10 and 18F-FDG were assessed in B16ova and B16ovaRevC3 cells after death-switch induction. Death-switch induction was confirmed in vivo in xenograft tumours, and 18F-ICMT-11 and 18F-ML-10 biodistribution was assessed by ex vivo gamma counting of select tissues. PET imaging was performed with 18F-ICMT-11, 18F-ML-10 and 18F-FDG. Caspase-3 activation was confirmed by immunohistochemistry. RESULTS: Significantly increased caspase-3/7 activity was observed only in B16ovaRevC3 cells after death-switch induction, accompanied by significantly increased 18F-ICMT-11 (p?<?0.001) and 18F-ML-10 (p?<?0.05) and decreased 18F-FDG (p?<?0.001) uptake compared with controls. B16ova and B16ovaRevC3 tumours had similar growth in vivo; however, B16ovaRevC3 growth was significantly reduced with death-switch induction (p?<?0.01). Biodistribution studies showed significantly increased 18F-ICMT-11 tumour uptake following death-switch induction (p?<?0.01), but not for 18F-ML-10. Tumour uptake of 18F-ICMT-11 was higher than that of 18F-ML-10 after death-switch induction. PET imaging studies showed that 18F-ICMT-11 can be used to detect apoptosis after death-switch induction, which was accompanied by significantly increased expression of cleaved caspase-3. 18F-FDG signal decreased in tumours after death-switch induction. CONCLUSIONS: We demonstrate that 18F-ICMT-11 can be used to detect caspase-3 activation in a death-switch tumour model, independent of the confounding effects of cancer therapeutics, thus confirming its specificity and supporting the development of this radiotracer for clinical use to monitor tumour apoptosis and therapy response.
CitationVassileva V, Stribbling S, Barnes C, Carroll L, Braga M, Abrahams J, et al. Evaluation of apoptosis imaging biomarkers in a genetic model of cell death. EJNMMI Res. 2019 Feb 19;9(1):18.
- Preclinical assessment of carboplatin treatment efficacy in lung cancer by 18F-ICMT-11-positron emission tomography.
- Authors: Witney TH, Fortt R, Aboagye EO
- Issue date: 2014
- Clinical translation of [<sup>18</sup>F]ICMT-11 for measuring chemotherapy-induced caspase 3/7 activation in breast and lung cancer.
- Authors: Dubash SR, Merchant S, Heinzmann K, Mauri F, Lavdas I, Inglese M, Kozlowski K, Rama N, Masrour N, Steel JF, Thornton A, Lim AK, Lewanski C, Cleator S, Coombes RC, Kenny L, Aboagye EO
- Issue date: 2018 Dec
- Temporal and spatial evolution of therapy-induced tumor apoptosis detected by caspase-3-selective molecular imaging.
- Authors: Nguyen QD, Lavdas I, Gubbins J, Smith G, Fortt R, Carroll LS, Graham MA, Aboagye EO
- Issue date: 2013 Jul 15
- 18F-ICMT-11, a caspase-3-specific PET tracer for apoptosis: biodistribution and radiation dosimetry.
- Authors: Challapalli A, Kenny LM, Hallett WA, Kozlowski K, Tomasi G, Gudi M, Al-Nahhas A, Coombes RC, Aboagye EO
- Issue date: 2013 Sep
- Depicting Changes in Tumor Biology in Response to Cetuximab Monotherapy or Combination Therapy by Apoptosis and Proliferation Imaging Using <sup>18</sup>F-ICMT-11 and <sup>18</sup>F-FLT PET.
- Authors: Heinzmann K, Nguyen QD, Honess D, Smith DM, Stribbling S, Brickute D, Barnes C, Griffiths J, Aboagye E
- Issue date: 2018 Oct