{"title":"使用[18F]PFPMD对非小细胞肺和结直肠癌癌症患者KRASG12C突变状态的首次人内PET成像。","authors":"Xiang Li, Jiajun Ye, Jingyi Wang, Zhiyong Quan, Guiyu Li, Wenhui Ma, Mingru Zhang, Weidong Yang, Junling Wang, Taoqi Ma, Fei Kang, Jing Wang","doi":"10.2967/jnumed.123.265715","DOIUrl":null,"url":null,"abstract":"<p><p>Kirsten rat sarcoma (<i>KRAS</i>) mutations are an important marker for tumor-targeted therapy. In this study, we sought to develop a KRAS<sup>G12C</sup> oncoprotein-targeted PET tracer and to evaluate its translational potential for noninvasive imaging of the <i>KRAS<sup>G12C</sup></i> mutation in non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) patients. <b>Methods:</b> [<sup>18</sup>F]PFPMD was synthesized on the basis of AMG510 (sotorasib) by attaching a polyethylene glycol chain to the quinazolinone structure. The binding selectivity and imaging potential of [<sup>18</sup>F]PFPMD were verified by cellular uptake, internalization, and blocking (H358: <i>KRAS<sup>G12C</sup></i> mutation; A549: non-<i>KRAS<sup>G12C</sup></i> mutation) studies, as well as by a small-animal PET/CT imaging study on tumor-bearing mice. Five healthy volunteers were enrolled to assess the safety, biodistribution, and dosimetry of [<sup>18</sup>F]PFPMD. Subsequently, 14 NSCLC or CRC patients with or without the <i>KRAS<sup>G12C</sup></i> mutation underwent [<sup>18</sup>F]PFPMD and [<sup>18</sup>F]FDG PET/CT imaging. The SUV<sub>max</sub> of tumor uptake of [<sup>18</sup>F]PFPMD was measured and compared between patients with and without the <i>KRAS<sup>G12C</sup></i> mutation. <b>Results:</b> [<sup>18</sup>F]PFPMD was obtained with a high radiochemical yield, radiochemical purity, and stability. The protein-binding assay showed that [<sup>18</sup>F]PFPMD selectively binds to the KRAS<sup>G12C</sup> protein. [<sup>18</sup>F]PFPMD uptake was significantly higher in H358 than in A549 and was decreased by pretreatment with AMG510 (H358 vs. A549: 3.22% ± 0.28% vs. 2.50% ± 0.25%, <i>P</i> < 0.05; block: 2.06% ± 0.13%, <i>P</i> < 0.01). Similar results were observed in tumor-bearing mice on PET imaging (H358 vs. A549: 3.93% ± 0.24% vs. 2.47% ± 0.26% injected dose/g, <i>P</i> < 0.01; block: 2.89% ± 0.29% injected dose/g; <i>P</i> < 0.05). [<sup>18</sup>F]PFPMD was safe in humans and was excreted primarily by the gallbladder and intestines. The whole-body effective dose was comparable to that of [<sup>18</sup>F]FDG. The accumulation of [<sup>18</sup>F]PFPMD in <i>KRAS<sup>G12C</sup></i> mutation tumors was significantly higher than that in non-<i>KRAS<sup>G12C</sup></i> mutation tumors (SUV<sub>max</sub>: 3.73 ± 0.58 vs. 2.39 ± 0.22, <i>P</i> < 0.01) in NSCLC and CRC patients. <b>Conclusion:</b> [<sup>18</sup>F]PFPMD is a safe and promising PET tracer for noninvasive screening of the <i>KRAS<sup>G12C</sup></i> mutation status in NSCLC and CRC patients.</p>","PeriodicalId":16758,"journal":{"name":"Journal of Nuclear Medicine","volume":" ","pages":"1880-1888"},"PeriodicalIF":9.1000,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"First-in-Humans PET Imaging of <i>KRAS<sup>G12C</sup></i> Mutation Status in Non-Small Cell Lung and Colorectal Cancer Patients Using [<sup>18</sup>F]PFPMD.\",\"authors\":\"Xiang Li, Jiajun Ye, Jingyi Wang, Zhiyong Quan, Guiyu Li, Wenhui Ma, Mingru Zhang, Weidong Yang, Junling Wang, Taoqi Ma, Fei Kang, Jing Wang\",\"doi\":\"10.2967/jnumed.123.265715\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Kirsten rat sarcoma (<i>KRAS</i>) mutations are an important marker for tumor-targeted therapy. In this study, we sought to develop a KRAS<sup>G12C</sup> oncoprotein-targeted PET tracer and to evaluate its translational potential for noninvasive imaging of the <i>KRAS<sup>G12C</sup></i> mutation in non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) patients. <b>Methods:</b> [<sup>18</sup>F]PFPMD was synthesized on the basis of AMG510 (sotorasib) by attaching a polyethylene glycol chain to the quinazolinone structure. The binding selectivity and imaging potential of [<sup>18</sup>F]PFPMD were verified by cellular uptake, internalization, and blocking (H358: <i>KRAS<sup>G12C</sup></i> mutation; A549: non-<i>KRAS<sup>G12C</sup></i> mutation) studies, as well as by a small-animal PET/CT imaging study on tumor-bearing mice. Five healthy volunteers were enrolled to assess the safety, biodistribution, and dosimetry of [<sup>18</sup>F]PFPMD. Subsequently, 14 NSCLC or CRC patients with or without the <i>KRAS<sup>G12C</sup></i> mutation underwent [<sup>18</sup>F]PFPMD and [<sup>18</sup>F]FDG PET/CT imaging. The SUV<sub>max</sub> of tumor uptake of [<sup>18</sup>F]PFPMD was measured and compared between patients with and without the <i>KRAS<sup>G12C</sup></i> mutation. <b>Results:</b> [<sup>18</sup>F]PFPMD was obtained with a high radiochemical yield, radiochemical purity, and stability. The protein-binding assay showed that [<sup>18</sup>F]PFPMD selectively binds to the KRAS<sup>G12C</sup> protein. [<sup>18</sup>F]PFPMD uptake was significantly higher in H358 than in A549 and was decreased by pretreatment with AMG510 (H358 vs. A549: 3.22% ± 0.28% vs. 2.50% ± 0.25%, <i>P</i> < 0.05; block: 2.06% ± 0.13%, <i>P</i> < 0.01). Similar results were observed in tumor-bearing mice on PET imaging (H358 vs. A549: 3.93% ± 0.24% vs. 2.47% ± 0.26% injected dose/g, <i>P</i> < 0.01; block: 2.89% ± 0.29% injected dose/g; <i>P</i> < 0.05). [<sup>18</sup>F]PFPMD was safe in humans and was excreted primarily by the gallbladder and intestines. The whole-body effective dose was comparable to that of [<sup>18</sup>F]FDG. The accumulation of [<sup>18</sup>F]PFPMD in <i>KRAS<sup>G12C</sup></i> mutation tumors was significantly higher than that in non-<i>KRAS<sup>G12C</sup></i> mutation tumors (SUV<sub>max</sub>: 3.73 ± 0.58 vs. 2.39 ± 0.22, <i>P</i> < 0.01) in NSCLC and CRC patients. <b>Conclusion:</b> [<sup>18</sup>F]PFPMD is a safe and promising PET tracer for noninvasive screening of the <i>KRAS<sup>G12C</sup></i> mutation status in NSCLC and CRC patients.</p>\",\"PeriodicalId\":16758,\"journal\":{\"name\":\"Journal of Nuclear Medicine\",\"volume\":\" \",\"pages\":\"1880-1888\"},\"PeriodicalIF\":9.1000,\"publicationDate\":\"2023-12-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Nuclear Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.2967/jnumed.123.265715\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Nuclear Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2967/jnumed.123.265715","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"RADIOLOGY, NUCLEAR MEDICINE & MEDICAL IMAGING","Score":null,"Total":0}
First-in-Humans PET Imaging of KRASG12C Mutation Status in Non-Small Cell Lung and Colorectal Cancer Patients Using [18F]PFPMD.
Kirsten rat sarcoma (KRAS) mutations are an important marker for tumor-targeted therapy. In this study, we sought to develop a KRASG12C oncoprotein-targeted PET tracer and to evaluate its translational potential for noninvasive imaging of the KRASG12C mutation in non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) patients. Methods: [18F]PFPMD was synthesized on the basis of AMG510 (sotorasib) by attaching a polyethylene glycol chain to the quinazolinone structure. The binding selectivity and imaging potential of [18F]PFPMD were verified by cellular uptake, internalization, and blocking (H358: KRASG12C mutation; A549: non-KRASG12C mutation) studies, as well as by a small-animal PET/CT imaging study on tumor-bearing mice. Five healthy volunteers were enrolled to assess the safety, biodistribution, and dosimetry of [18F]PFPMD. Subsequently, 14 NSCLC or CRC patients with or without the KRASG12C mutation underwent [18F]PFPMD and [18F]FDG PET/CT imaging. The SUVmax of tumor uptake of [18F]PFPMD was measured and compared between patients with and without the KRASG12C mutation. Results: [18F]PFPMD was obtained with a high radiochemical yield, radiochemical purity, and stability. The protein-binding assay showed that [18F]PFPMD selectively binds to the KRASG12C protein. [18F]PFPMD uptake was significantly higher in H358 than in A549 and was decreased by pretreatment with AMG510 (H358 vs. A549: 3.22% ± 0.28% vs. 2.50% ± 0.25%, P < 0.05; block: 2.06% ± 0.13%, P < 0.01). Similar results were observed in tumor-bearing mice on PET imaging (H358 vs. A549: 3.93% ± 0.24% vs. 2.47% ± 0.26% injected dose/g, P < 0.01; block: 2.89% ± 0.29% injected dose/g; P < 0.05). [18F]PFPMD was safe in humans and was excreted primarily by the gallbladder and intestines. The whole-body effective dose was comparable to that of [18F]FDG. The accumulation of [18F]PFPMD in KRASG12C mutation tumors was significantly higher than that in non-KRASG12C mutation tumors (SUVmax: 3.73 ± 0.58 vs. 2.39 ± 0.22, P < 0.01) in NSCLC and CRC patients. Conclusion: [18F]PFPMD is a safe and promising PET tracer for noninvasive screening of the KRASG12C mutation status in NSCLC and CRC patients.
期刊介绍:
The Journal of Nuclear Medicine (JNM), self-published by the Society of Nuclear Medicine and Molecular Imaging (SNMMI), provides readers worldwide with clinical and basic science investigations, continuing education articles, reviews, employment opportunities, and updates on practice and research. In the 2022 Journal Citation Reports (released in June 2023), JNM ranked sixth in impact among 203 medical journals worldwide in the radiology, nuclear medicine, and medical imaging category.