Evaluation of apoptosis imaging biomarkers in a genetic model of cell death

Vessela Vassileva, Stephen M. Stribbling, Chris Barnes, Laurence Carroll, Marta Braga, Joel Abrahams, Kathrin Heinzmann, Caroline Haegeman, Marion MacFarlane, Kathryn L. Simpson, Caroline Dive, Jamie Honeychurch, Timothy M. Illidge, Eric O. Aboagye

Research output: Contribution to journalArticle

Abstract

Purpose: We have previously developed the caspase-based radiotracer, 18 F-ICMT-11, for PET imaging to monitor treatment response. We further validated 18 F-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 18 F-ICMT-11, 18 F-ML-10 and 18 F-FDG were assessed in B16ova and B16ovaRevC3 cells after death-switch induction. Death-switch induction was confirmed in vivo in xenograft tumours, and 18 F-ICMT-11 and 18 F-ML-10 biodistribution was assessed by ex vivo gamma counting of select tissues. PET imaging was performed with 18 F-ICMT-11, 18 F-ML-10 and 18 F-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 18 F-ICMT-11 (p < 0.001) and 18 F-ML-10 (p < 0.05) and decreased 18 F-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 18 F-ICMT-11 tumour uptake following death-switch induction (p < 0.01), but not for 18 F-ML-10. Tumour uptake of 18 F-ICMT-11 was higher than that of 18 F-ML-10 after death-switch induction. PET imaging studies showed that 18 F-ICMT-11 can be used to detect apoptosis after death-switch induction, which was accompanied by significantly increased expression of cleaved caspase-3. 18 F-FDG signal decreased in tumours after death-switch induction. Conclusions: We demonstrate that 18 F-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.

Original languageEnglish (US)
Article number18
JournalEJNMMI Research
Volume9
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

Fingerprint

Genetic Models
Cell Death
Biomarkers
Apoptosis
Caspase 3
Neoplasms
Caspase 7
(18)F-ICMT11
Doxycycline
Therapeutic Uses
Growth
Caspases
Heterografts
Melanoma
Immunohistochemistry

Keywords

  • F-ICMT-11
  • Apoptosis
  • Caspases
  • Death-switch
  • Molecular imaging
  • PET
  • Radiotracer

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging

Cite this

Vassileva, V., Stribbling, S. M., Barnes, C., Carroll, L., Braga, M., Abrahams, J., ... Aboagye, E. O. (2019). Evaluation of apoptosis imaging biomarkers in a genetic model of cell death. EJNMMI Research, 9, [18]. https://doi.org/10.1186/s13550-019-0487-8

Evaluation of apoptosis imaging biomarkers in a genetic model of cell death. / Vassileva, Vessela; Stribbling, Stephen M.; Barnes, Chris; Carroll, Laurence; Braga, Marta; Abrahams, Joel; Heinzmann, Kathrin; Haegeman, Caroline; MacFarlane, Marion; Simpson, Kathryn L.; Dive, Caroline; Honeychurch, Jamie; Illidge, Timothy M.; Aboagye, Eric O.

In: EJNMMI Research, Vol. 9, 18, 01.01.2019.

Research output: Contribution to journalArticle

Vassileva, V, Stribbling, SM, Barnes, C, Carroll, L, Braga, M, Abrahams, J, Heinzmann, K, Haegeman, C, MacFarlane, M, Simpson, KL, Dive, C, Honeychurch, J, Illidge, TM & Aboagye, EO 2019, 'Evaluation of apoptosis imaging biomarkers in a genetic model of cell death', EJNMMI Research, vol. 9, 18. https://doi.org/10.1186/s13550-019-0487-8
Vassileva, Vessela ; Stribbling, Stephen M. ; Barnes, Chris ; Carroll, Laurence ; Braga, Marta ; Abrahams, Joel ; Heinzmann, Kathrin ; Haegeman, Caroline ; MacFarlane, Marion ; Simpson, Kathryn L. ; Dive, Caroline ; Honeychurch, Jamie ; Illidge, Timothy M. ; Aboagye, Eric O. / Evaluation of apoptosis imaging biomarkers in a genetic model of cell death. In: EJNMMI Research. 2019 ; Vol. 9.
@article{9b75866421b74a0c915a7712209744f6,
title = "Evaluation of apoptosis imaging biomarkers in a genetic model of cell death",
abstract = "Purpose: We have previously developed the caspase-based radiotracer, 18 F-ICMT-11, for PET imaging to monitor treatment response. We further validated 18 F-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 18 F-ICMT-11, 18 F-ML-10 and 18 F-FDG were assessed in B16ova and B16ovaRevC3 cells after death-switch induction. Death-switch induction was confirmed in vivo in xenograft tumours, and 18 F-ICMT-11 and 18 F-ML-10 biodistribution was assessed by ex vivo gamma counting of select tissues. PET imaging was performed with 18 F-ICMT-11, 18 F-ML-10 and 18 F-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 18 F-ICMT-11 (p < 0.001) and 18 F-ML-10 (p < 0.05) and decreased 18 F-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 18 F-ICMT-11 tumour uptake following death-switch induction (p < 0.01), but not for 18 F-ML-10. Tumour uptake of 18 F-ICMT-11 was higher than that of 18 F-ML-10 after death-switch induction. PET imaging studies showed that 18 F-ICMT-11 can be used to detect apoptosis after death-switch induction, which was accompanied by significantly increased expression of cleaved caspase-3. 18 F-FDG signal decreased in tumours after death-switch induction. Conclusions: We demonstrate that 18 F-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.",
keywords = "F-ICMT-11, Apoptosis, Caspases, Death-switch, Molecular imaging, PET, Radiotracer",
author = "Vessela Vassileva and Stribbling, {Stephen M.} and Chris Barnes and Laurence Carroll and Marta Braga and Joel Abrahams and Kathrin Heinzmann and Caroline Haegeman and Marion MacFarlane and Simpson, {Kathryn L.} and Caroline Dive and Jamie Honeychurch and Illidge, {Timothy M.} and Aboagye, {Eric O.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1186/s13550-019-0487-8",
language = "English (US)",
volume = "9",
journal = "EJNMMI Research",
issn = "2191-219X",
publisher = "Springer Berlin",

}

TY - JOUR

T1 - Evaluation of apoptosis imaging biomarkers in a genetic model of cell death

AU - Vassileva, Vessela

AU - Stribbling, Stephen M.

AU - Barnes, Chris

AU - Carroll, Laurence

AU - Braga, Marta

AU - Abrahams, Joel

AU - Heinzmann, Kathrin

AU - Haegeman, Caroline

AU - MacFarlane, Marion

AU - Simpson, Kathryn L.

AU - Dive, Caroline

AU - Honeychurch, Jamie

AU - Illidge, Timothy M.

AU - Aboagye, Eric O.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Purpose: We have previously developed the caspase-based radiotracer, 18 F-ICMT-11, for PET imaging to monitor treatment response. We further validated 18 F-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 18 F-ICMT-11, 18 F-ML-10 and 18 F-FDG were assessed in B16ova and B16ovaRevC3 cells after death-switch induction. Death-switch induction was confirmed in vivo in xenograft tumours, and 18 F-ICMT-11 and 18 F-ML-10 biodistribution was assessed by ex vivo gamma counting of select tissues. PET imaging was performed with 18 F-ICMT-11, 18 F-ML-10 and 18 F-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 18 F-ICMT-11 (p < 0.001) and 18 F-ML-10 (p < 0.05) and decreased 18 F-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 18 F-ICMT-11 tumour uptake following death-switch induction (p < 0.01), but not for 18 F-ML-10. Tumour uptake of 18 F-ICMT-11 was higher than that of 18 F-ML-10 after death-switch induction. PET imaging studies showed that 18 F-ICMT-11 can be used to detect apoptosis after death-switch induction, which was accompanied by significantly increased expression of cleaved caspase-3. 18 F-FDG signal decreased in tumours after death-switch induction. Conclusions: We demonstrate that 18 F-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.

AB - Purpose: We have previously developed the caspase-based radiotracer, 18 F-ICMT-11, for PET imaging to monitor treatment response. We further validated 18 F-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 18 F-ICMT-11, 18 F-ML-10 and 18 F-FDG were assessed in B16ova and B16ovaRevC3 cells after death-switch induction. Death-switch induction was confirmed in vivo in xenograft tumours, and 18 F-ICMT-11 and 18 F-ML-10 biodistribution was assessed by ex vivo gamma counting of select tissues. PET imaging was performed with 18 F-ICMT-11, 18 F-ML-10 and 18 F-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 18 F-ICMT-11 (p < 0.001) and 18 F-ML-10 (p < 0.05) and decreased 18 F-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 18 F-ICMT-11 tumour uptake following death-switch induction (p < 0.01), but not for 18 F-ML-10. Tumour uptake of 18 F-ICMT-11 was higher than that of 18 F-ML-10 after death-switch induction. PET imaging studies showed that 18 F-ICMT-11 can be used to detect apoptosis after death-switch induction, which was accompanied by significantly increased expression of cleaved caspase-3. 18 F-FDG signal decreased in tumours after death-switch induction. Conclusions: We demonstrate that 18 F-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.

KW - F-ICMT-11

KW - Apoptosis

KW - Caspases

KW - Death-switch

KW - Molecular imaging

KW - PET

KW - Radiotracer

UR - http://www.scopus.com/inward/record.url?scp=85061769499&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85061769499&partnerID=8YFLogxK

U2 - 10.1186/s13550-019-0487-8

DO - 10.1186/s13550-019-0487-8

M3 - Article

C2 - 30783791

AN - SCOPUS:85061769499

VL - 9

JO - EJNMMI Research

JF - EJNMMI Research

SN - 2191-219X

M1 - 18

ER -