胶原型I型PET/MRI可以评估胰腺癌前和首次人类翻译研究中胰腺癌的治疗反应

胰腺导管腺癌（PDAC）是一种侵入性和快速进行性恶性肿瘤。患者管理中的主要挑战是缺乏可靠的成像工具来监测肿瘤对治疗的反应。具有高I胶原蛋白特征的肿瘤相关纤维化是PDAC的标志，纤维化进一步增加了对新辅助化学疗法（CRT）的响应。我们假设使用I型胶原特异性成像探针的分子正电子发射断层扫描（PET），68GA-CBP8可以在小鼠模型和PDAC患者的标准治疗中检测并测量肿瘤纤维化的变化。方法：我们根据人类PDAC裸鼠模型的动态变化（包括Folfirnox-敏感性（PANC-1和PDAC6）（PDAC6）和Folfirinox-Resistant-Resistant（Su.86.86.86.86），基于纤维化的动态变化，我们评估了68GA-CBP8 PET对肿瘤胶原蛋白的特异性及其与非反应者区分开的能力。接下来，我们证明了在切除的人PDAC和胰腺组织中对沉积胶原蛋白的68GA-CBP8的特异性和敏感性。八名男性参与者（49-65岁），新诊断的PDAC接受了动态68GA-CBP8 PET/MRI，并在完成标准CRT后进行了68GA-CBP8 PET/MRI。 PET参数与肿瘤胶原蛋白含量和组织学反应标记相关。结果：与非结合68GA-CNBP探针相比，在PET成像的两种小鼠模型中，68GA-CBP8与非结合68GA-CNBP探针相比显示出特异性的结合，并使用放射自显影（用于所有比较的p <0.05）。在Panc-1和PDAC6模型中，68GA-CBP8 PET在小鼠模型中显示出2倍的肿瘤信号（P <0.01），但在FOLFIRINOX抗性SU.86.86模型中处理后没有显着增加。在处理过的组织与未处理的组织中，与切除的人PDAC的结合68GA-CBP8与切除的人PDAC的结合明显更高（p <0.0001）。与胰腺相比，CRT前PDAC患者的PET/MRI在肿瘤中显示出明显更高的68GA-CBP8摄取（SUVMEAN：2.35±0.36 vs. 1.99±0.25，p = 0.036，n = 8）。与未处理的肿瘤相比，CRT后的PET肿瘤值显着增加（Suvmean：2.83±0.30 vs. 2.25±0.41，p = 0.01，n = 5）。胶原蛋白沉积显着增加，对CRT的响应显着增加（59±9％vs. 30±9％，P = 0.0005在处理过的肿瘤与未治疗的肿瘤中）。肿瘤和胰腺胶原蛋白含量显示与SUVMEAN的正直接相关性（R2 = 0.54，P = 0.0007）。结论：这项研究表明，基于PDAC中纤维化的动态变化，68GA-CBP8 PET对I型肿瘤I型胶原蛋白的特异性及其将反应者与非反应者区分开的能力。结果突出了胶原蛋白宠物作为非侵入性工具的潜在用途，用于监测PDAC患者对治疗的反应。

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.