Preclinical Evaluation of <sup>18</sup>F-ML-10 to Determine Timing of Apoptotic Response to Chemotherapy in Solid Tumors

Demirci, Emre; Ahmed, Rafay; Ocak, Meltem; Latoche, Joseph D.; Radelet, April; DeBlasio, Nicole; Mason, N. Scott; Anderson, Carolyn J.; Mountz, James M.

doi:10.1177/1536012116685941

Cited by 15 publications

(10 citation statements)

References 35 publications

(80 reference statements)

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“…We did not confirm the absence of fixation of [ 18 F]ML-10 to the necrotic cells. However, this was largely demonstrated by several teams [18,19,22]. Our results show, for the first time, that [ 18 F]ML-10 indeed targets TNBC cells in early apoptosis after paclitaxel treatment in vitro.…”

Section: Discussionmentioning

confidence: 55%

“…The authors confirmed the value of PET imaging with [ 18 F]ML-10 for early assessment of tumor response to therapy as well as the potential of this radiotracer to visualize apoptosis. In addition, studies in two types of solid tumors (nasopharyngeal carcinoma and head/neck carcinoma) have also highlighted the capacity of the [ 18 F]ML-10 radiotracer to target apoptotic cells following cancer chemotherapy [22,23]. However, no pre-clinical or clinical studies have been conducted in TNBC models.…”

Section: Introductionmentioning

confidence: 99%

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[18F]ML-10 PET imaging fails to assess early response to neoadjuvant chemotherapy in a preclinical model of triple negative breast cancer

et al. 2020

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Purpose: Pathological complete response to the neoadjuvant therapy (NAT) for triple negative breast cancer (TNBC) is predictive of prolonged patient survival. Methods for early evaluation of NAT efficiency are still needed, in order to rapidly adjust the therapeutic strategy in case of initial non-response. One option for this is molecular imaging of apoptosis induced by chemotherapy. Therefore, we investigated the capacity of [ 18 F]ML-10 PET imaging, an apoptosis radiotracer, to detect tumor cell apoptosis and early predict the therapeutic response of human TNBC.Results: Initially, the induction of apoptosis by different therapies was quantified. We confirmed, in vitro, that paclitaxel or epirubicin, the fundamental cytotoxic drugs for breast cancer, induce apoptosis in TNBC cell lines. Exposure of TNBC models MDA-MB-231 and MDA-MB-468 to these drugs induced a significant increase (p < 0.01) of the apoptotic hallmarks: DNA fragmentation, membrane phospholipid scrambling, and PARP activation. Secondarily, apoptotic fraction was compared to the intracellular accumulation of the radiotracer. [ 18 F]ML-10 accumulated in the apoptotic cells after 72 h of treatment by paclitaxel in vitro; this accumulation positively correlated with the apoptotic fraction. In vivo, [ 18 F]ML-10 was rapidly cleared from the nontarget organs and mainly eliminated by the kidneys. Comparison of the in vivo [ 18 F]FDG, [ 18 F]FMISO, and [ 18 F]ML-10 uptakes revealed that the tumor accumulation of [ 18 F]ML-10 was directly related to the tumor hypoxia level. Finally, after the in vivo treatment of TNBC murine xenografts by paclitaxel, apoptosis was well induced, as demonstrated by the cleaved caspase-3 levels; however, no significant increase of [ 18 F]ML-10 accumulation in the tumors was observed, either on day 3 or day 6 after the end of the treatment.Conclusions: These results highlighted that PET imaging using [ 18 F]ML-10 allows the visualization of apoptotic cells in TNBC models. Nevertheless, the increase of the chemotherapy-induced apoptotic response when using paclitaxel could not be assessed using this radiotracer in our mouse model.

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Section: Discussionmentioning

confidence: 55%

Section: Introductionmentioning

confidence: 99%

[18F]ML-10 PET imaging fails to assess early response to neoadjuvant chemotherapy in a preclinical model of triple negative breast cancer

et al. 2020

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“…Of note, a recent study demonstrated an increased uptake of 18 F-ML-18 after doxorubicin administration in head and neck tumour xenografts at 3 and 7 days post-treatment, but with minimal change at day 1 [33]. However, the authors did not correlate these findings to caspase-3 activity; instead, the TUNEL assay was used for the assessment of apoptosis, which is a measure of the apoptotic process at a later stage.…”

Section: Discussionmentioning

confidence: 99%

“…PET imaging using the apoptotic radiotracers, 18 F-ICMT-11 and 18 F-ML-10, and the gold-standard 18 F-FDG radiotracer was conducted in mice with B16ova and B16ovaRevC3 tumour xenografts 24 h after vehicle-control or doxycycline administration (as above for biodistribution studies), using parameters based on previous radiotracer distribution studies [14, 17, 33, 34]. Table 1 provides a summary of the radiotracers (specific activities, injected doses and volumes).…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2019

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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. Electronic supplementary material The online version of this article (10.1186/s13550-019-0487-8) contains supplementary material, which is available to authorized users.

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“…Following the radiation treatment of human nasopharyngeal carcinoma xenografts (highly differentiated xenografts CNE1 and poorly differentiated xenografts CNE2), the tumour to muscle ratios were statistically different at both 24 and 48 h in CNE1 and CNE2 mice (ratios in CNE2 xeongrafts being higher than those in CNE1 xenografts) [ 44 ]. In another study on nude mice implanted with UM-SCC-22B tumours that were treated with two doses of doxorubicin by Demirci et al, the tumour to liver ratios of 18 F-ML-10 proved to be significantly higher at days 3 and 7 post-treatment but not on day 1 [ 45 ]. The imaging potential of 18 F-ML-10 was also assessed in human volunteers and patients [ 46 ].…”

Section: Cell Membrane Acidification Targeting Radioligandsmentioning

confidence: 99%

Apoptosis Imaging in Oncology by Means of Positron Emission Tomography: A Review

Wiele

Ustmert

Spiegeleer

et al. 2021

IJMS

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To date, a wide variety of potential PET-apoptosis imaging radiopharmaceuticals targeting apoptosis-induced cell membrane asymmetry and acidification, as well as caspase 3 activation (substrates and inhibitors) have been developed with the purpose of rapidly assessing the response to treatment in cancer patients. Many of these probes were shown to specifically bind to their apoptotic target in vitro and their uptake to be enhanced in the in vivo-xenografted tumours in mice treated by means of chemotherapy, however, to a significantly variable degree. This may, in part, relate to the tumour model used given the fact that different tumour cell lines bear a different sensitivity to a similar chemotherapeutic agent, to differences in the chemotherapeutic concentration and exposure time, as well as to the different timing of imaging performed post-treatment. The best validated cell membrane acidification and caspase 3 targeting radioligands, respectively 18F-ML-10 from the Aposense family and the radiolabelled caspase 3 substrate 18F-CP18, have also been injected in healthy individuals and shown to bear favourable dosimetric and safety characteristics. However, in contrast to, for instance, the 99mTc-HYNIC-Annexin V, neither of both tracers was taken up to a significant degree by the bone marrow in the healthy individuals under study. Removal of white and red blood cells from the bone marrow through apoptosis plays a major role in the maintenance of hematopoietic cell homeostasis. The major apoptotic population in normal bone marrow are immature erythroblasts. While an accurate estimate of the number of immature erythroblasts undergoing apoptosis is not feasible due to their unknown clearance rate, their number is likely substantial given the ineffective quote of the erythropoietic process described in healthy subjects. Thus, the clinical value of both 18F-ML-10 and 18F-CP18 for apoptosis imaging in cancer patients, as suggested by a small number of subsequent clinical phase I/II trials in patients suffering from primary or secondary brain malignancies using 18F-ML-10 and in an ongoing trial in patients suffering from cancer of the ovaries using 18F-CP18, remains to be proven and warrants further investigation.

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Preclinical Evaluation of ¹⁸F-ML-10 to Determine Timing of Apoptotic Response to Chemotherapy in Solid Tumors

Cited by 15 publications

References 35 publications

[18F]ML-10 PET imaging fails to assess early response to neoadjuvant chemotherapy in a preclinical model of triple negative breast cancer

[18F]ML-10 PET imaging fails to assess early response to neoadjuvant chemotherapy in a preclinical model of triple negative breast cancer

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

Apoptosis Imaging in Oncology by Means of Positron Emission Tomography: A Review

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Preclinical Evaluation of 18F-ML-10 to Determine Timing of Apoptotic Response to Chemotherapy in Solid Tumors

Cited by 15 publications

References 35 publications

[18F]ML-10 PET imaging fails to assess early response to neoadjuvant chemotherapy in a preclinical model of triple negative breast cancer

[18F]ML-10 PET imaging fails to assess early response to neoadjuvant chemotherapy in a preclinical model of triple negative breast cancer

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

Apoptosis Imaging in Oncology by Means of Positron Emission Tomography: A Review

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Preclinical Evaluation of ¹⁸F-ML-10 to Determine Timing of Apoptotic Response to Chemotherapy in Solid Tumors