Yanina Dockx, Christel Vangestel, Tim Van den Wyngaert, Manon Huizing, Sven De Bruycker, Patrick Pauwels, Steven Staelens, Sigrid Stroobants
{"title":"[18F]FDG摄取在her -2阳性肿瘤异种移植中作为PI3K/Akt/mTOR靶向药物的早期变化","authors":"Yanina Dockx, Christel Vangestel, Tim Van den Wyngaert, Manon Huizing, Sven De Bruycker, Patrick Pauwels, Steven Staelens, Sigrid Stroobants","doi":"10.1155/2021/5594514","DOIUrl":null,"url":null,"abstract":"<p><p>We investigated the potential use of [<sup>18</sup>F]FDG PET as a response biomarker for PI3K pathway targeting therapies in two HER-2-overexpressing cancer models. <i>Methods</i>. CD-1 nude mice were inoculated with HER-2-overexpressing JIMT1 (trastuzumab-resistant) or SKOV3 (trastuzumab-sensitive) human cancer cells. Animals were treated with trastuzumab, everolimus (mTOR inhibitor), PIK90 (PI3K inhibitor), saline, or combination therapy. [<sup>18</sup>F]FDG scans were performed at baseline, two, and seven days after the start of the therapy. Tumors were delineated on CT images and relative tumor volumes (RTV) and maximum standardized uptake value (SUV<sub>max</sub>) were calculated. Levels of pS6 and pAkt on protein tumor lysates were determined with ELISA. <i>Results</i>. In the SKOV3 xenografts, all treatment schedules resulted in a gradual decrease in RTV and delta SUV<sub>max</sub> (<i>Δ</i>SUV<sub>max</sub>). For all treatments combined, <i>Δ</i>SUV<sub>max</sub> after 2 days was predictive for RTV after 7 days (<i>r</i> = 0.69, <i>p</i> = 0.030). In JIMT1 tumors, monotherapy with everolimus or PIK90 resulted in a decrease in RTV (-30% ± 10% and -20% ± 20%, respectively) and <i>Δ</i>SUV<sub>max</sub> (-39% ± 36% and -42% ± 8%, respectively) after 7 days of treatment, but not earlier, while trastuzumab resulted in nonsignificant increases compared to control. Combination therapies resulted in RTV and <i>Δ</i>SUV<sub>max</sub> decrease already at day 2, except for trastuzumab+everolimus, where an early flare was observed. For all treatments combined, <i>Δ</i>SUV<sub>max</sub> after 2 days was predictive for RTV after 7 days (<i>r</i> = 0.48, <i>p</i> = 0.028), but the correlation could be improved when combination with everolimus (<i>r</i> = 0.59, <i>p</i> = 0.023) or trastuzumab (<i>r</i> = 0.69, <i>p</i> = 0.015) was excluded. <i>Conclusion</i>. Reduction in [<sup>18</sup>F]FDG after 2 days correlated with tumor volume changes after 7 days of treatment and confirms the use of [<sup>18</sup>F]FDG PET as an early response biomarker. Treatment response can however be underestimated in schedules containing trastuzumab or everolimus due to temporary increased [<sup>18</sup>F]FDG uptake secondary to negative feedback loop and crosstalk between different pathways.</p>","PeriodicalId":18855,"journal":{"name":"Molecular Imaging","volume":null,"pages":null},"PeriodicalIF":2.2000,"publicationDate":"2021-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169268/pdf/","citationCount":"3","resultStr":"{\"title\":\"Early Changes in [<sup>18</sup>F]FDG Uptake as a Readout for PI3K/Akt/mTOR Targeted Drugs in HER-2-Positive Cancer Xenografts.\",\"authors\":\"Yanina Dockx, Christel Vangestel, Tim Van den Wyngaert, Manon Huizing, Sven De Bruycker, Patrick Pauwels, Steven Staelens, Sigrid Stroobants\",\"doi\":\"10.1155/2021/5594514\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>We investigated the potential use of [<sup>18</sup>F]FDG PET as a response biomarker for PI3K pathway targeting therapies in two HER-2-overexpressing cancer models. <i>Methods</i>. CD-1 nude mice were inoculated with HER-2-overexpressing JIMT1 (trastuzumab-resistant) or SKOV3 (trastuzumab-sensitive) human cancer cells. Animals were treated with trastuzumab, everolimus (mTOR inhibitor), PIK90 (PI3K inhibitor), saline, or combination therapy. [<sup>18</sup>F]FDG scans were performed at baseline, two, and seven days after the start of the therapy. Tumors were delineated on CT images and relative tumor volumes (RTV) and maximum standardized uptake value (SUV<sub>max</sub>) were calculated. Levels of pS6 and pAkt on protein tumor lysates were determined with ELISA. <i>Results</i>. In the SKOV3 xenografts, all treatment schedules resulted in a gradual decrease in RTV and delta SUV<sub>max</sub> (<i>Δ</i>SUV<sub>max</sub>). For all treatments combined, <i>Δ</i>SUV<sub>max</sub> after 2 days was predictive for RTV after 7 days (<i>r</i> = 0.69, <i>p</i> = 0.030). In JIMT1 tumors, monotherapy with everolimus or PIK90 resulted in a decrease in RTV (-30% ± 10% and -20% ± 20%, respectively) and <i>Δ</i>SUV<sub>max</sub> (-39% ± 36% and -42% ± 8%, respectively) after 7 days of treatment, but not earlier, while trastuzumab resulted in nonsignificant increases compared to control. Combination therapies resulted in RTV and <i>Δ</i>SUV<sub>max</sub> decrease already at day 2, except for trastuzumab+everolimus, where an early flare was observed. For all treatments combined, <i>Δ</i>SUV<sub>max</sub> after 2 days was predictive for RTV after 7 days (<i>r</i> = 0.48, <i>p</i> = 0.028), but the correlation could be improved when combination with everolimus (<i>r</i> = 0.59, <i>p</i> = 0.023) or trastuzumab (<i>r</i> = 0.69, <i>p</i> = 0.015) was excluded. <i>Conclusion</i>. Reduction in [<sup>18</sup>F]FDG after 2 days correlated with tumor volume changes after 7 days of treatment and confirms the use of [<sup>18</sup>F]FDG PET as an early response biomarker. Treatment response can however be underestimated in schedules containing trastuzumab or everolimus due to temporary increased [<sup>18</sup>F]FDG uptake secondary to negative feedback loop and crosstalk between different pathways.</p>\",\"PeriodicalId\":18855,\"journal\":{\"name\":\"Molecular Imaging\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.2000,\"publicationDate\":\"2021-05-25\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169268/pdf/\",\"citationCount\":\"3\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular Imaging\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1155/2021/5594514\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2021/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q3\",\"JCRName\":\"BIOCHEMICAL RESEARCH METHODS\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Imaging","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1155/2021/5594514","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2021/1/1 0:00:00","PubModel":"eCollection","JCR":"Q3","JCRName":"BIOCHEMICAL RESEARCH METHODS","Score":null,"Total":0}
引用次数: 3
摘要
我们研究了[18F]FDG PET作为两种her -2过表达癌症模型中PI3K通路靶向治疗的反应性生物标志物的潜在用途。方法。用her -2过表达的JIMT1(曲妥珠单抗耐药)或SKOV3(曲妥珠单抗敏感)人癌细胞接种CD-1裸鼠。动物接受曲妥珠单抗、依维莫司(mTOR抑制剂)、PIK90 (PI3K抑制剂)、生理盐水或联合治疗。[18F]在治疗开始后的基线、第2天和第7天进行FDG扫描。在CT图像上圈定肿瘤，计算相对肿瘤体积(RTV)和最大标准化摄取值(SUVmax)。ELISA法检测肿瘤蛋白裂解物中pS6和pAkt的表达水平。结果。在SKOV3异种移植物中，所有治疗方案都导致RTV和delta SUVmax逐渐降低(ΔSUVmax)。对于所有联合治疗，2天后ΔSUVmax可预测7天后的RTV (r = 0.69, p = 0.030)。在JIMT1肿瘤中，依维莫司或PIK90单药治疗导致治疗7天后RTV(分别为-30%±10%和-20%±20%)和ΔSUVmax(分别为-39%±36%和-42%±8%)下降，但不早，而曲妥珠单抗导致与对照组相比无显著增加。联合治疗导致RTV和ΔSUVmax在第2天已经下降，除了曲妥珠单抗+依维莫司，观察到早期发作。对于所有联合治疗，2天后ΔSUVmax可预测7天后的RTV (r = 0.48, p = 0.028)，但当排除依维莫司(r = 0.59, p = 0.023)或曲妥珠单抗(r = 0.69, p = 0.015)时，相关性可以得到改善。结论。2天后[18F]FDG的减少与治疗7天后肿瘤体积的变化相关，证实了[18F]FDG PET作为早期反应生物标志物的使用。然而，在含有曲妥珠单抗或依维莫司的方案中，由于负反馈回路和不同通路之间的串扰导致FDG摄取暂时增加[18F]，治疗反应可能被低估。
Early Changes in [18F]FDG Uptake as a Readout for PI3K/Akt/mTOR Targeted Drugs in HER-2-Positive Cancer Xenografts.
We investigated the potential use of [18F]FDG PET as a response biomarker for PI3K pathway targeting therapies in two HER-2-overexpressing cancer models. Methods. CD-1 nude mice were inoculated with HER-2-overexpressing JIMT1 (trastuzumab-resistant) or SKOV3 (trastuzumab-sensitive) human cancer cells. Animals were treated with trastuzumab, everolimus (mTOR inhibitor), PIK90 (PI3K inhibitor), saline, or combination therapy. [18F]FDG scans were performed at baseline, two, and seven days after the start of the therapy. Tumors were delineated on CT images and relative tumor volumes (RTV) and maximum standardized uptake value (SUVmax) were calculated. Levels of pS6 and pAkt on protein tumor lysates were determined with ELISA. Results. In the SKOV3 xenografts, all treatment schedules resulted in a gradual decrease in RTV and delta SUVmax (ΔSUVmax). For all treatments combined, ΔSUVmax after 2 days was predictive for RTV after 7 days (r = 0.69, p = 0.030). In JIMT1 tumors, monotherapy with everolimus or PIK90 resulted in a decrease in RTV (-30% ± 10% and -20% ± 20%, respectively) and ΔSUVmax (-39% ± 36% and -42% ± 8%, respectively) after 7 days of treatment, but not earlier, while trastuzumab resulted in nonsignificant increases compared to control. Combination therapies resulted in RTV and ΔSUVmax decrease already at day 2, except for trastuzumab+everolimus, where an early flare was observed. For all treatments combined, ΔSUVmax after 2 days was predictive for RTV after 7 days (r = 0.48, p = 0.028), but the correlation could be improved when combination with everolimus (r = 0.59, p = 0.023) or trastuzumab (r = 0.69, p = 0.015) was excluded. Conclusion. Reduction in [18F]FDG after 2 days correlated with tumor volume changes after 7 days of treatment and confirms the use of [18F]FDG PET as an early response biomarker. Treatment response can however be underestimated in schedules containing trastuzumab or everolimus due to temporary increased [18F]FDG uptake secondary to negative feedback loop and crosstalk between different pathways.
Molecular ImagingBiochemistry, Genetics and Molecular Biology-Biotechnology
自引率
3.60%
发文量
21
期刊介绍：
Molecular Imaging is a peer-reviewed, open access journal highlighting the breadth of molecular imaging research from basic science to preclinical studies to human applications. This serves both the scientific and clinical communities by disseminating novel results and concepts relevant to the biological study of normal and disease processes in both basic and translational studies ranging from mice to humans.
![Early Changes in [<sup>18</sup>F]FDG Uptake as a Readout for PI3K/Akt/mTOR Targeted Drugs in HER-2-Positive Cancer Xenografts.](https://img.booksci.cn/booksciimg/2021-5/2023110778234782415267540874536.jpg)
![Early Changes in [<sup>18</sup>F]FDG Uptake as a Readout for PI3K/Akt/mTOR Targeted Drugs in HER-2-Positive Cancer Xenografts.](https://img.booksci.cn/booksciimg/2021-5/202311077823616123128072725751.jpg)
![Early Changes in [<sup>18</sup>F]FDG Uptake as a Readout for PI3K/Akt/mTOR Targeted Drugs in HER-2-Positive Cancer Xenografts.](https://img.booksci.cn/booksciimg/2021-5/2023110778255178895671800114639.jpg)
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
