Ma Hua, Esfahani Shadi A, Krishna Shriya, Ataeinia Bahar, Zhou Iris Y, Rotile Nicholas J, Weigand-Whittier Jonah, Boice Avery T, Liss Andrew S, Tanabe Kenneth K, Caravan Peter
Department of Radiology, Institute for Innovation in Imaging (i3), Massachusetts General Hospital, Charlestown, Massachusetts.
Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, Massachusetts.
Cancer Res. 2024 Aug 1;84(15):2549-2560. doi: 10.1158/0008-5472.CAN-23-3548.
Neoadjuvant therapy is routinely used in pancreatic ductal adenocarcinoma (PDAC), but not all tumors respond to this treatment. Current clinical imaging techniques are not able to precisely evaluate and predict the response to neoadjuvant therapies over several weeks. A strong fibrotic reaction is a hallmark of a positive response, and during fibrogenesis, allysine residues are formed on collagen proteins by the action of lysyl oxidases. Here, we report the application of an allysine-targeted molecular MRI probe, MnL3, to provide an early, noninvasive assessment of treatment response in PDAC. Allysine increased 2- to 3-fold after one dose of neoadjuvant therapy with FOLFIRINOX in sensitive human PDAC xenografts in mice. Molecular MRI with MnL3 could specifically detect and quantify fibrogenesis in PDAC xenografts. Comparing the MnL3 signal before and 3 days after one dose of FOLFIRINOX predicted subsequent treatment response. The MnL3 tumor signal increased by 70% from day 0 to day 3 in mice that responded to subsequent doses of FOLFIRINOX, whereas no signal increase was observed in FOLFIRINOX-resistant tumors. This study indicates the promise of allysine-targeted molecular MRI as a noninvasive tool to predict chemotherapy outcomes. Significance: Allysine-targeted molecular MRI can quantify fibrogenesis in pancreatic tumors and predict response to chemotherapy, which could guide rapid clinical management decisions by differentiating responders from nonresponders after treatment initiation.
新辅助治疗常用于胰腺导管腺癌（PDAC），但并非所有肿瘤都对这种治疗有反应。目前的临床成像技术无法在数周内精确评估和预测对新辅助治疗的反应。强烈的纤维化反应是阳性反应的标志，在纤维生成过程中，赖氨酰氧化酶作用于胶原蛋白上形成烯赖氨酸残基。在此，我们报告了一种靶向烯赖氨酸的分子磁共振成像（MRI）探针MnL3的应用，以对PDAC的治疗反应进行早期、非侵入性评估。在对FOLFIRINOX敏感的人PDAC小鼠异种移植模型中，一剂新辅助治疗FOLFIRINOX后，烯赖氨酸增加了2至3倍。使用MnL3的分子MRI能够特异性地检测和量化PDAC异种移植模型中的纤维生成。比较一剂FOLFIRINOX治疗前和治疗后3天的MnL3信号可预测后续治疗反应。在对后续剂量FOLFIRINOX有反应的小鼠中，MnL3肿瘤信号从第0天到第3天增加了70%，而在对FOLFIRINOX耐药的肿瘤中未观察到信号增加。这项研究表明，靶向烯赖氨酸的分子MRI有望成为一种预测化疗结果的非侵入性工具。意义：靶向烯赖氨酸的分子MRI可以量化胰腺肿瘤中的纤维生成并预测化疗反应，通过在治疗开始后区分反应者和无反应者，这可以指导快速的临床管理决策。
