Shadi A Esfahani, Hua Ma, Shriya Krishna, Sergey Shuvaev, Mark Sabbagh, Caitlin Deffler, Nicholas Rotile, Jonah Weigand-Whittier, Iris Y Zhou, Ciprian Catana, Onofrio A Catalano, David T Ting, Pedram Heidari, Eric Abston, Michael Lanuti, Genevieve M Boland, Priyanka Pathak, Hannah Roberts, Kenneth K Tanabe, Motaz Qadan, Carlos Fernandez-Del Castillo, Angela Shih, Aparna R Parikh, Colin D Weekes, Theodore S Hong, Peter Caravan
{"title":"胶原 I 型 PET/MRI 能够在临床前研究和首次人体转化研究中评估胰腺癌的治疗反应。","authors":"Shadi A Esfahani, Hua Ma, Shriya Krishna, Sergey Shuvaev, Mark Sabbagh, Caitlin Deffler, Nicholas Rotile, Jonah Weigand-Whittier, Iris Y Zhou, Ciprian Catana, Onofrio A Catalano, David T Ting, Pedram Heidari, Eric Abston, Michael Lanuti, Genevieve M Boland, Priyanka Pathak, Hannah Roberts, Kenneth K Tanabe, Motaz Qadan, Carlos Fernandez-Del Castillo, Angela Shih, Aparna R Parikh, Colin D Weekes, Theodore S Hong, Peter Caravan","doi":"10.7150/thno.100116","DOIUrl":null,"url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is an invasive and rapidly progressive malignancy. A major challenge in patient management is the lack of a reliable imaging tool to monitor tumor response to treatment. Tumor-associated fibrosis characterized by high type I collagen is a hallmark of PDAC, and fibrosis further increases in response to neoadjuvant chemoradiotherapy (CRT). We hypothesized that molecular positron emission tomography (PET) using a type I collagen-specific imaging probe, <sup>68</sup>Ga-CBP8 can detect and measure changes in tumor fibrosis in response to standard treatment in mouse models and patients with PDAC. <b>Methods:</b> We evaluated the specificity of <sup>68</sup>Ga-CBP8 PET to tumor collagen and its ability to differentiate responders from non-responders based on the dynamic changes of fibrosis in nude mouse models of human PDAC including FOLFIRNOX-sensitive (PANC-1 and PDAC6) and FOLFIRINOX-resistant (SU.86.86). Next, we demonstrated the specificity and sensitivity of <sup>68</sup>Ga-CBP8 to the deposited collagen in resected human PDAC and pancreas tissues. Eight male participant (49-65 y) with newly diagnosed PDAC underwent dynamic <sup>68</sup>Ga-CBP8 PET/MRI, and five underwent follow up <sup>68</sup>Ga-CBP8 PET/MRI after completing standard CRT. PET parameters were correlated with tumor collagen content and markers of response on histology. <b>Results:</b> <sup>68</sup>Ga-CBP8 showed specific binding to PDAC compared to non-binding <sup>68</sup>Ga-CNBP probe in two mouse models of PDAC using PET imaging and to resected human PDAC using autoradiography (P < 0.05 for all comparisons). <sup>68</sup>Ga-CBP8 PET showed 2-fold higher tumor signal in mouse models following FOLFIRINOX treatment in PANC-1 and PDAC6 models (P < 0.01), but no significant increase after treatment in FOLFIRINOX resistant SU.86.86 model. <sup>68</sup>Ga-CBP8 binding to resected human PDAC was significantly higher (P < 0.0001) in treated versus untreated tissue. PET/MRI of PDAC patients prior to CRT showed significantly higher <sup>68</sup>Ga-CBP8 uptake in tumor compared to pancreas (SUV<sub>mean</sub>: 2.35 ± 0.36 vs. 1.99 ± 0.25, P = 0.036, n = 8). PET tumor values significantly increased following CRT compared to untreated tumors (SUV<sub>mean</sub>: 2.83 ± 0.30 vs. 2.25 ± 0.41, P = 0.01, n = 5). Collagen deposition significantly increased in response to CRT (59 ± 9% vs. 30 ± 9%, P=0.0005 in treated vs. untreated tumors). Tumor and pancreas collagen content showed a positive direct correlation with SUV<sub>mean</sub> (R<sup>2</sup> = 0.54, P = 0.0007). <b>Conclusions:</b> This study demonstrates the specificity of <sup>68</sup>Ga-CBP8 PET to tumor type I collagen and its ability to differentiate responders from non-responders based on the dynamic changes of fibrosis in PDAC. The results highlight the potential use of collagen PET as a non-invasive tool for monitoring response to treatment in patients with PDAC.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4000,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11426233/pdf/","citationCount":"0","resultStr":"{\"title\":\"Collagen type I PET/MRI enables evaluation of treatment response in pancreatic cancer in pre-clinical and first-in-human translational studies.\",\"authors\":\"Shadi A Esfahani, Hua Ma, Shriya Krishna, Sergey Shuvaev, Mark Sabbagh, Caitlin Deffler, Nicholas Rotile, Jonah Weigand-Whittier, Iris Y Zhou, Ciprian Catana, Onofrio A Catalano, David T Ting, Pedram Heidari, Eric Abston, Michael Lanuti, Genevieve M Boland, Priyanka Pathak, Hannah Roberts, Kenneth K Tanabe, Motaz Qadan, Carlos Fernandez-Del Castillo, Angela Shih, Aparna R Parikh, Colin D Weekes, Theodore S Hong, Peter Caravan\",\"doi\":\"10.7150/thno.100116\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Pancreatic ductal adenocarcinoma (PDAC) is an invasive and rapidly progressive malignancy. A major challenge in patient management is the lack of a reliable imaging tool to monitor tumor response to treatment. Tumor-associated fibrosis characterized by high type I collagen is a hallmark of PDAC, and fibrosis further increases in response to neoadjuvant chemoradiotherapy (CRT). We hypothesized that molecular positron emission tomography (PET) using a type I collagen-specific imaging probe, <sup>68</sup>Ga-CBP8 can detect and measure changes in tumor fibrosis in response to standard treatment in mouse models and patients with PDAC. <b>Methods:</b> We evaluated the specificity of <sup>68</sup>Ga-CBP8 PET to tumor collagen and its ability to differentiate responders from non-responders based on the dynamic changes of fibrosis in nude mouse models of human PDAC including FOLFIRNOX-sensitive (PANC-1 and PDAC6) and FOLFIRINOX-resistant (SU.86.86). Next, we demonstrated the specificity and sensitivity of <sup>68</sup>Ga-CBP8 to the deposited collagen in resected human PDAC and pancreas tissues. Eight male participant (49-65 y) with newly diagnosed PDAC underwent dynamic <sup>68</sup>Ga-CBP8 PET/MRI, and five underwent follow up <sup>68</sup>Ga-CBP8 PET/MRI after completing standard CRT. PET parameters were correlated with tumor collagen content and markers of response on histology. <b>Results:</b> <sup>68</sup>Ga-CBP8 showed specific binding to PDAC compared to non-binding <sup>68</sup>Ga-CNBP probe in two mouse models of PDAC using PET imaging and to resected human PDAC using autoradiography (P < 0.05 for all comparisons). <sup>68</sup>Ga-CBP8 PET showed 2-fold higher tumor signal in mouse models following FOLFIRINOX treatment in PANC-1 and PDAC6 models (P < 0.01), but no significant increase after treatment in FOLFIRINOX resistant SU.86.86 model. <sup>68</sup>Ga-CBP8 binding to resected human PDAC was significantly higher (P < 0.0001) in treated versus untreated tissue. PET/MRI of PDAC patients prior to CRT showed significantly higher <sup>68</sup>Ga-CBP8 uptake in tumor compared to pancreas (SUV<sub>mean</sub>: 2.35 ± 0.36 vs. 1.99 ± 0.25, P = 0.036, n = 8). PET tumor values significantly increased following CRT compared to untreated tumors (SUV<sub>mean</sub>: 2.83 ± 0.30 vs. 2.25 ± 0.41, P = 0.01, n = 5). Collagen deposition significantly increased in response to CRT (59 ± 9% vs. 30 ± 9%, P=0.0005 in treated vs. untreated tumors). Tumor and pancreas collagen content showed a positive direct correlation with SUV<sub>mean</sub> (R<sup>2</sup> = 0.54, P = 0.0007). <b>Conclusions:</b> This study demonstrates the specificity of <sup>68</sup>Ga-CBP8 PET to tumor type I collagen and its ability to differentiate responders from non-responders based on the dynamic changes of fibrosis in PDAC. The results highlight the potential use of collagen PET as a non-invasive tool for monitoring response to treatment in patients with PDAC.</p>\",\"PeriodicalId\":22932,\"journal\":{\"name\":\"Theranostics\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":12.4000,\"publicationDate\":\"2024-09-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11426233/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Theranostics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.7150/thno.100116\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Theranostics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.7150/thno.100116","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
摘要
胰腺导管腺癌(PDAC)是一种侵袭性、进展迅速的恶性肿瘤。患者管理面临的一大挑战是缺乏可靠的成像工具来监测肿瘤对治疗的反应。以高 I 型胶原蛋白为特征的肿瘤相关纤维化是 PDAC 的标志,而纤维化在对新辅助化放疗(CRT)的反应中进一步加重。我们假设,使用 I 型胶原蛋白特异性成像探针 68Ga-CBP8 进行分子正电子发射断层扫描(PET)可以检测和测量小鼠模型和 PDAC 患者在接受标准治疗时肿瘤纤维化的变化。方法我们评估了 68Ga-CBP8 PET 对肿瘤胶原蛋白的特异性及其根据 FOLFIRNOX 敏感(PANC-1 和 PDAC6)和 FOLFIRINOX 耐药(SU.86.86)等人类 PDAC 裸鼠模型中纤维化的动态变化区分应答者和非应答者的能力。接下来,我们证明了 68Ga-CBP8 对切除的人类 PDAC 和胰腺组织中沉积的胶原蛋白的特异性和敏感性。八名新诊断为 PDAC 的男性患者(49-65 岁)接受了动态 68Ga-CBP8 PET/MRI,五名患者在完成标准 CRT 后接受了 68Ga-CBP8 PET/MRI 随访。PET 参数与肿瘤胶原蛋白含量和组织学反应标记物相关。结果显示在两个PDAC小鼠模型中,68Ga-CBP8通过PET成像与PDAC特异性结合,与不结合的68Ga-CNBP探针相比,68Ga-CBP8与PDAC特异性结合;在切除的人类PDAC中,68Ga-CBP8通过自体放射成像与PDAC特异性结合(所有比较中P<0.05)。68Ga-CBP8 PET显示,在PANC-1和PDAC6模型中,FOLFIRINOX治疗后小鼠模型的肿瘤信号增加了2倍(P < 0.01),但在FOLFIRINOX耐药的SU.86.86模型中,FOLFIRINOX治疗后肿瘤信号没有显著增加。与未治疗的组织相比,68Ga-CBP8 与切除的人 PDAC 的结合率明显更高(P < 0.0001)。PDAC患者在接受CRT治疗前的PET/MRI显示,肿瘤对68Ga-CBP8的摄取明显高于胰腺(SUVmean:2.35 ± 0.36 vs. 1.99 ± 0.25,P = 0.036,n = 8)。与未治疗的肿瘤相比,CRT 后 PET 肿瘤值明显增加(SUVmean:2.83 ± 0.30 vs. 2.25 ± 0.41,P = 0.01,n = 5)。胶原沉积对 CRT 的反应明显增加(59 ± 9% vs. 30 ± 9%,治疗肿瘤 vs. 未治疗肿瘤,P=0.0005)。肿瘤和胰腺胶原蛋白含量与 SUVmean 值呈直接正相关(R2 = 0.54,P = 0.0007)。结论本研究证明了 68Ga-CBP8 PET 对肿瘤 I 型胶原蛋白的特异性及其根据 PDAC 纤维化的动态变化区分有反应者和无反应者的能力。结果凸显了胶原蛋白 PET 作为一种非侵入性工具用于监测 PDAC 患者治疗反应的潜力。
Collagen type I PET/MRI enables evaluation of treatment response in pancreatic cancer in pre-clinical and first-in-human translational studies.
Pancreatic ductal adenocarcinoma (PDAC) is an invasive and rapidly progressive malignancy. A major challenge in patient management is the lack of a reliable imaging tool to monitor tumor response to treatment. Tumor-associated fibrosis characterized by high type I collagen is a hallmark of PDAC, and fibrosis further increases in response to neoadjuvant chemoradiotherapy (CRT). We hypothesized that molecular positron emission tomography (PET) using a type I collagen-specific imaging probe, 68Ga-CBP8 can detect and measure changes in tumor fibrosis in response to standard treatment in mouse models and patients with PDAC. Methods: We evaluated the specificity of 68Ga-CBP8 PET to tumor collagen and its ability to differentiate responders from non-responders based on the dynamic changes of fibrosis in nude mouse models of human PDAC including FOLFIRNOX-sensitive (PANC-1 and PDAC6) and FOLFIRINOX-resistant (SU.86.86). Next, we demonstrated the specificity and sensitivity of 68Ga-CBP8 to the deposited collagen in resected human PDAC and pancreas tissues. Eight male participant (49-65 y) with newly diagnosed PDAC underwent dynamic 68Ga-CBP8 PET/MRI, and five underwent follow up 68Ga-CBP8 PET/MRI after completing standard CRT. PET parameters were correlated with tumor collagen content and markers of response on histology. Results:68Ga-CBP8 showed specific binding to PDAC compared to non-binding 68Ga-CNBP probe in two mouse models of PDAC using PET imaging and to resected human PDAC using autoradiography (P < 0.05 for all comparisons). 68Ga-CBP8 PET showed 2-fold higher tumor signal in mouse models following FOLFIRINOX treatment in PANC-1 and PDAC6 models (P < 0.01), but no significant increase after treatment in FOLFIRINOX resistant SU.86.86 model. 68Ga-CBP8 binding to resected human PDAC was significantly higher (P < 0.0001) in treated versus untreated tissue. PET/MRI of PDAC patients prior to CRT showed significantly higher 68Ga-CBP8 uptake in tumor compared to pancreas (SUVmean: 2.35 ± 0.36 vs. 1.99 ± 0.25, P = 0.036, n = 8). PET tumor values significantly increased following CRT compared to untreated tumors (SUVmean: 2.83 ± 0.30 vs. 2.25 ± 0.41, P = 0.01, n = 5). Collagen deposition significantly increased in response to CRT (59 ± 9% vs. 30 ± 9%, P=0.0005 in treated vs. untreated tumors). Tumor and pancreas collagen content showed a positive direct correlation with SUVmean (R2 = 0.54, P = 0.0007). Conclusions: This study demonstrates the specificity of 68Ga-CBP8 PET to tumor type I collagen and its ability to differentiate responders from non-responders based on the dynamic changes of fibrosis in PDAC. The results highlight the potential use of collagen PET as a non-invasive tool for monitoring response to treatment in patients with PDAC.
期刊介绍:
Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.