胶原蛋白I型PET/MRI在胰腺癌预临床和首例人类转化研究中的治疗反应评估

胰腺导管腺癌（PDAC）是一种侵袭性强、进展迅速的恶性肿瘤。患者管理中的一大难题是缺乏可靠的成像工具以监测肿瘤对治疗的反应。由高表达I型胶原蛋白的肿瘤相关纤维化是PDAC的标志，而纤维化在新辅助放化疗（CRT）后进一步加重。我们假设，使用特异性胶原蛋白I型成像探针68Ga-CBP8的分子正电子发射断层扫描（PET）可以检测并衡量肿瘤纤维化的变化，以评估在小鼠模型和PDAC患者中对标准治疗的反应。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纤维化变化区分反应者与非反应者的能力，包括在FOLFIRNOX敏感（PANC-1和PDAC6）和FOLFIRINOX耐药（SU.86.86）的人源性PDAC裸鼠模型中的动态变化。接着，我们验证了68Ga-CBP8对切除的人类PDAC及胰腺组织中沉积胶原的特异性和敏感性。8名新诊断PDAC男性患者（49-65岁）接受动态68Ga-CBP8 PET/MRI，另有5名患者在完成标准CRT后进行随访PET/MRI。PET参数与肿瘤胶原含量及组织学反应标志物相关分析。结果：68Ga-CBP8在两个PDAC鼠模型中显示出对PDAC的特异性结合（相较非结合性68Ga-CNBP探针，P < 0.05），并通过自放射照相确认其在切除的患者PDAC中具有显著结合（P < 0.0001）。在FOLFIRINOX治疗后，PANC-1和PDAC6模型中的肿瘤信号提高了2倍（P < 0.01），而耐药模型SU.86.86未见明显变化。治疗组中，68Ga-CBP8对人类PDAC的结合显著高于未治疗组织（P < 0.0001）。在CRT前的PDAC患者中，肿瘤的68Ga-CBP8摄取显著高于胰腺（SUV平均值：2.35 ± 0.36对1.99 ± 0.25，P = 0.036，n=8），CRT后肿瘤的摄取显著增加（SUV平均值：2.83 ± 0.30对2.25 ± 0.41，P = 0.01，n=5）。胶原沉积在CRT反应组中显著增加（59 ± 9%对30 ± 9%，P=0.0005）。肿瘤和胰腺的胶原含量与SUV平均值呈正相关（R^2=0.54，P=0.0007）。结论：本研究证明了68Ga-CBP8 PET对肿瘤I型胶原的特异性及其基于纤维化动态变化区分反应者和非反应者的能力，显示胶原PET作为一种非侵入性监测PDAC治疗反应的潜在工具。

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.