Dataset Information

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

ABSTRACT:

Purpose

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?18F-ML-10 (p?18F-FDG (p?18F-ICMT-11 tumour uptake following death-switch induction (p?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.

SUBMITTER: Vassileva V

PROVIDER: S-EPMC6381199 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Publications

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

Vassileva Vessela V Stribbling Stephen M SM Barnes Chris C Carroll Laurence L Braga Marta M Abrahams Joel J Heinzmann Kathrin K Haegeman Caroline C MacFarlane Marion M Simpson Kathryn L KL Dive Caroline C Honeychurch Jamie J Illidge Timothy M TM Aboagye Eric O EO

EJNMMI research 20190219 1

<h4>Purpose</h4>We have previously developed the caspase-based radiotracer, <sup>18</sup>F-ICMT-11, for PET imaging to monitor treatment response. We further validated <sup>18</sup>F-ICMT-11 specificity in a murine melanoma death-switch tumour model with conditional activation of caspase-3 induced by doxycycline.<h4>Methods</h4>Caspase-3/7 activity and cellular uptake of <sup>18</sup>F-ICMT-11, <sup>18</sup>F-ML-10 and <sup>18</sup>F-FDG were assessed in B16ova and B16ovaRevC3 cells after death- ...[more]

PMID: 30783791

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Project description:PurposeApoptosis, in the context of cancer, is a form of programmed cell death induced by chemotherapy, radiotherapy, and immunotherapy. As this is a central pathway in treatment response, considerable effort has been expended on the development of molecular imaging agents to non-invasively measure tumor apoptosis prior to quantitative changes in tumor dimensions. Despite these efforts, clinical trials directed at imaging apoptosis by PET, SPECT, and MRI have failed to robustly predict response to treatment with high sensitivity and specificity. Although these shortcomings may be linked to probe design, we propose that the combination of variability in the timing of maximal in vivo tumor apoptosis and sub-optimal sampling times fundamentally limits the predictive power of PET/SPECT apoptosis imaging.ProceduresHerein, we surveyed the literature describing the time course of therapy-induced tumor apoptosis in vivo and used these data to construct a mathematical model describing the onset, duration, amplitude, and variability of the apoptotic response. Uncertainty in the underlying time of initiation of tumor apoptosis was simulated by Gaussian, uniform, and Landau distributions centered at the median time-to-maximum apoptotic rate derived from the literature. We then computationally sampled these models for various durations to simulate PET/SPECT imaging agents with variable effective half-lives.ResultsModels with a narrow Gaussian distribution of initiation times for tumor apoptosis predicted high contrast ratios and strong predictive values for all effective tracer half-lives. However, when uncertainty in apoptosis initiation times were simulated with uniform and Landau distributions, high contrast ratios and predictive values were only obtained with extremely long imaging windows (days). The imaging contrast ratios predicted in these models were consistent with those seen in pre-clinical apoptosis PET/SPECT imaging studies and suggest that uncertainty in the timing of tumor cell death plays a significant role in the maximal contrast obtainable. Moreover, when uncertainty in both apoptosis initiation and imaging start times were simulated, the predicted contrast ratios were dramatically reduced for all tracer half-lives.ConclusionsThese studies illustrate the effect of uncertainty of apoptosis initiation on the predictive power of PET/SPECT apoptosis imaging agents and suggest that long integration times are required to surmount uncertainty in the time domain of this biological process.

Dataset Information

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

Purpose

Methods

Results

Conclusions

Publications

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

Similar Datasets

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