Comparing the use of radiolabeled SSTR agonists and an SSTR antagonist in breast cancer: does the model choice influence the outcome?,EJNMMI Radiopharmacy and Chemistry

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Comparing the use of radiolabeled SSTR agonists and an SSTR antagonist in breast cancer: does the model choice influence the outcome?
EJNMMI Radiopharmacy and Chemistry ( IF 4.4 ) Pub Date : 2017-09-29 , DOI: 10.1186/s41181-017-0030-z
Simone U Dalm ₁ , Marion de Jong ₁

Affiliation

With interest we read the recent publication of Dude et al. (2017) on the evaluation of somatostatin receptor (SSTR) agonists and an antagonist for SSTR-mediated imaging of breast cancer using positron emission tomography. In this study the authors compared 2 SSTR agonists (DOTA-Tyr³-octreotide and DOTA-Tyr³-octreotate) and the SSTR antagonist (NODAGA-JR11) in in vitro binding and saturation studies and in in vivo imaging and biodistribution studies. To our surprise their results demonstrated both agonists to have a more favorable receptor binding affinity and a better tumor uptake in vivo, whereas the saturation assay resulted in more binding sites for ^67/natGa-DOTA-Tyr³-octreotide on the used breast cancer cell line (ZR75–1) than ^natGa-NODAGA-JR11 and ^67/natGa-DOTA-Tyr³-octreotate.

The reported results are in contrast with previously published studies comparing radiolabeled DOTA-Tyr³-octreotate and DOTA-JR11 in various tumor models (Dalm et al., 2016; Nicolas et al., 2017; Reubi et al., 2017; Wild et al., 2014), including our recent publication on the use of SSTR agonists and antagonists for targeting of breast cancer (Dalm et al., 2017). The main explanation given by the authors for the contradicting results is the use of an endogenously SSTR expressing breast cancer cell line, ZR75–1, in contrast to transfected cell lines, cell lines of other cancer types and non-cancerous cell lines used in earlier studies evaluating SSTR-targeting radiotracers.

Concerning the above mentioned explanation of the authors, we have the following remarks:

First, some of the non-cancerous cell lines and cell lines of other cancer types used in previous studies also have endogenous SSTR expression. One example is our previously published study in which we reported better therapeutic efficacy with ¹⁷⁷Lu-DOTA-JR11 compared to ¹⁷⁷Lu-DOTA-Tyr³-octreotate in a xenograft model generated with the human small cell lung cancer cell line, H69 (Dalm et al., 2016).
Furthermore, previously published studies comparing the use of radiolabeled JR11 and radiolabeled DOTA-Tyr³-octreotate or DOTA-Tyr³-octreotide were not only performed preclinically in tumor models, but also clinically in patients with neuroendocrine tumors. In the latter mentioned study published by Wild et al. (2014) ¹⁷⁷Lu-DOTA-JR11 tumor uptake was superior to that of ¹⁷⁷Lu-DOTA-Tyr³-octreotate. Although this study was not performed in breast cancer patients, it again demonstrates superiority of the SSTR antagonist vs the agonist in tumors that have endogenous SSTR expression.
Concerning breast cancer, Reubi et al. (2017) demonstrated that binding of ¹²⁵I–DOTA-JR11 to human breast cancer tissue was much higher than that of ¹²⁵I–DOTA-Tyr³-octreotide. We also demonstrated higher binding of ¹¹¹In-DOTA-JR11 vs ¹¹¹In-DOTA-Tyr³-octreotate to 40 human breast cancer tissue samples (Dalm et al., 2017). Furthermore, in the same study we also showed higher in vivo tumor uptake of ¹⁷⁷Lu-DOTA-JR11 vs ¹⁷⁷Lu-DOTA-Tyr³-octreotate in an estrogen receptor positive patient derived breast cancer mouse model with endogenous SSTR expression.

Differences between the study of Dude et al. (2017) and our previous study (Dalm et al., 2017) include the use of different radionuclides and application of DOTA-JR11 instead of NODAGA-JR11. The authors chose NODAGA-JR11 because DOTA-JR11 has a lower receptor affinity when labeled with ⁶⁸Ga. Similar to ¹¹¹In-DOTA-JR11, ¹⁷⁷Lu-DOTA-JR11 and ¹⁷⁷Lu-DOTA-Tyr³-octreotate, ⁶⁸Ga-NODAGA-JR11, ⁶⁸Ga-DOTA-Tyr³-octreotate and ⁶⁸Ga-DOTA-Tyr³-octreotide have comparable receptor affinity (Fani et al., 2012; Reubi et al., 2000).

Aspects concerning the methodology that to our opinion might influence the results when comparing different radiotracers, include:

The use of different peptide amounts as also addressed by the authors in the discussion. The peptide amount of ⁶⁸Ga-DOTA-Tyr³-octreotate used in the study was twice as high as the peptide amount of ⁶⁸Ga-NODAGA-JR11. Although the authors mention that previous studies showed that within a range of 10–60 pmol tumor uptake of ¹¹¹In-DOTA-Tyr³-octreotide is >80% of the maximum in rats (de Jong et al., 1999), this might be different in the model currently applied and this needs to be determined for the other radiotracers as well.
The use of different peptide amounts for imaging and biodistribution studies.
The use of an agonist (SRIF-28) in the competition assay to determine the binding affinity of the tracers. This would only be correct if the antagonist and the agonist have the same binding site, which is unclear.
Also, in the study by Dude et al. (2017) imaging and biodistribution studies were performed at early time points (55 min and 60 min p.i., respectively), presumably because of the short half-life of ⁶⁸Ga. However, in another study by Nicolas et al. (2017) it was reported that optimal tumor uptake of ¹⁷⁷Lu-DOTA-JR11 and ¹⁷⁷Lu-DOTA-Tyr³-octreotate was reached at 4 h p.i. as determined by biodistribution studies. Although there might be a difference in optimal tumor uptake when the same tracer is labeled with different radionuclides, the time point at which the imaging and biodistribution studies were performed might have contributed to the contradictory findings reported by in the study by Dude et al. (2017).

We recently compared binding of ¹¹¹In-DOTA-JR11 and ¹¹¹In-DOTA-Tyr³-octreotate to ZR75–1 and U2OS + SSTR2 (the latter is a human osteosarcoma cell line transfected with the SSTR2 receptor) in an internalization assay to investigate differences in SSTR agonist and antagonist binding to cell lines with endogenous and exogenous SSTR expression. The used method can be found in our previous paper (Dalm et al., 2016). Our results demonstrated that ¹¹¹In-DOTA-JR11 is superior to ¹¹¹In-DOTA-Tyr³-octreotate (even though the agonist is internalized) when applied for targeting of an endogenous SSTR-expressing cell line (ZR75–1) as well as for targeting the SSTR2 transfected cell line (Fig. 1).

Based on the above we conclude that endogenous SSTR expression of the model used in the study by Dude et al. (2017) does not explain the contradictory results obtained in this study. Multiple experiments in their study had a similar outcome and additional experiments are needed to determine what the reason is for these findings. However, in line with previous studies from our and other groups, the SSTR antagonist JR11 clearly shows superiority to the SSTR agonist octreotate for targeting breast cancer, also in the endogenously SSTR2 expressing breast cancer cell line ZR75–1.

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The publication of this article was supported by funds of the European Association of Nuclear Medicine (EANM).

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No funding was received for writing this letter or performing the experiments described in this letter. The publication costs were covered by the European Association of Nuclear Medicine.

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Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, South Holland, Netherlands
Simone U. Dalm & Marion de Jong

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Dalm, S.U., de Jong, M. Comparing the use of radiolabeled SSTR agonists and an SSTR antagonist in breast cancer: does the model choice influence the outcome?. EJNMMI radiopharm. chem. 2, 11 (2017). https://doi.org/10.1186/s41181-017-0030-z

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Received: 28 July 2017
Accepted: 03 September 2017
Published: 29 September 2017
DOI: https://doi.org/10.1186/s41181-017-0030-z

中文翻译：

比较放射标记的 SSTR 激动剂和 SSTR 拮抗剂在乳腺癌中的使用：模型选择是否会影响结果？

我们饶有兴趣地阅读了 Dude 等人最近发表的文章。 ( 2017 ) 使用正电子发射断层扫描评估生长抑素受体 (SSTR) 激动剂和拮抗剂对 SSTR 介导的乳腺癌成像的影响。在这项研究中，作者在体外结合和饱和研究以及体内成像和生物分布研究中比较了 2 种 SSTR 激动剂（DOTA-Tyr ^{3 -}奥曲肽和 DOTA-Tyr ^{3 -}奥曲肽）和 SSTR 拮抗剂 (NODAGA-JR11)。令我们惊讶的是，他们的结果表明两种激动剂都具有更有利的受体结合亲和力和更好的体内肿瘤摄取，而饱和测定导致^67/nat Ga-DOTA-Tyr ³ -octreotide 在所用乳腺癌上有更多的结合位点细胞系 (ZR75–1) 优于^nat Ga-NODAGA-JR11 和^67/nat Ga-DOTA-Tyr ³ -octreotate。

报告的结果与之前发表的在各种肿瘤模型中比较放射性标记的 DOTA-Tyr ³ -octreotate 和 DOTA-JR11 的研究形成鲜明对比（Dalm 等人， 2016 年；Nicolas 等人， 2017 年；Reubi 等人， 2017 年；Wild 等人） al.， 2014 ），包括我们最近发表的关于使用 SSTR 激动剂和拮抗剂靶向乳腺癌的出版物（Dalm 等， 2017 ）。作者对矛盾结果给出的主要解释是使用了内源性表达 SSTR 的乳腺癌细胞系 ZR75-1，与早期使用的转染细胞系、其他癌症类型的细胞系和非癌细胞系形成鲜明对比。评估 SSTR 靶向放射性示踪剂的研究。

针对作者的上述解释，我们有如下评论：

首先，之前研究中使用的一些非癌细胞系和其他癌症类型的细胞系也具有内源性SSTR表达。一个例子是我们之前发表的研究，其中我们报道了在人类小细胞肺癌细胞系 H69 (Dalm) 生成的异种移植模型中， ¹⁷⁷ Lu-DOTA-JR11 的治疗效果优于¹⁷⁷ Lu-DOTA-Tyr ³ -octreotate。等人， 2016 ）。
Furthermore, previously published studies comparing the use of radiolabeled JR11 and radiolabeled DOTA-Tyr³-octreotate or DOTA-Tyr³-octreotide were not only performed preclinically in tumor models, but also clinically in patients with neuroendocrine tumors. In the latter mentioned study published by Wild et al. (2014) ¹⁷⁷Lu-DOTA-JR11 tumor uptake was superior to that of ¹⁷⁷Lu-DOTA-Tyr³-octreotate. Although this study was not performed in breast cancer patients, it again demonstrates superiority of the SSTR antagonist vs the agonist in tumors that have endogenous SSTR expression.
Concerning breast cancer, Reubi et al. (2017) demonstrated that binding of ¹²⁵I–DOTA-JR11 to human breast cancer tissue was much higher than that of ¹²⁵I–DOTA-Tyr³-octreotide. We also demonstrated higher binding of ¹¹¹In-DOTA-JR11 vs ¹¹¹In-DOTA-Tyr³-octreotate to 40 human breast cancer tissue samples (Dalm et al., 2017). Furthermore, in the same study we also showed higher in vivo tumor uptake of ¹⁷⁷Lu-DOTA-JR11 vs ¹⁷⁷Lu-DOTA-Tyr³-octreotate in an estrogen receptor positive patient derived breast cancer mouse model with endogenous SSTR expression.

我们认为在比较不同放射性示踪剂时可能影响结果的方法方面包括：

The use of different peptide amounts as also addressed by the authors in the discussion. The peptide amount of ⁶⁸Ga-DOTA-Tyr³-octreotate used in the study was twice as high as the peptide amount of ⁶⁸Ga-NODAGA-JR11. Although the authors mention that previous studies showed that within a range of 10–60 pmol tumor uptake of ¹¹¹In-DOTA-Tyr³-octreotide is >80% of the maximum in rats (de Jong et al., 1999), this might be different in the model currently applied and this needs to be determined for the other radiotracers as well.
使用不同的肽量进行成像和生物分布研究。
在竞争测定中使用激动剂 (SRIF-28) 来确定示踪剂的结合亲和力。只有当拮抗剂和激动剂具有相同的结合位点时，这才是正确的，但目前尚不清楚。
Also, in the study by Dude et al. (2017) imaging and biodistribution studies were performed at early time points (55 min and 60 min p.i., respectively), presumably because of the short half-life of ⁶⁸Ga. However, in another study by Nicolas et al. (2017) it was reported that optimal tumor uptake of ¹⁷⁷Lu-DOTA-JR11 and ¹⁷⁷Lu-DOTA-Tyr³-octreotate was reached at 4 h p.i. as determined by biodistribution studies. Although there might be a difference in optimal tumor uptake when the same tracer is labeled with different radionuclides, the time point at which the imaging and biodistribution studies were performed might have contributed to the contradictory findings reported by in the study by Dude et al. (2017).

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