Esfahani Shadi A, Ma Li, Krishna Shriya, Ma Hua, Raheem Shvan J, Shuvaev Sergey, Rotile Nicholas J, Weigand-Whittier Jonah, Boice Avery T, Borges Nicholas, Treaba Constantina A, Deffler Caitlin, Diyabalanage Himashinie, Humblet Valerie, Sosnovik David E, Mahmood Umar, Heidari Pedram, Shih Angela, Catana Ciprian, Strickland Matthew R, Klempner Samuel J, Caravan Peter
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Division of Nuclear Medicine and Molecular Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Sci Transl Med. 2024 Dec 11;16(777):eadn7218. doi: 10.1126/scitranslmed.adn7218.
Patients with advanced gastric cancer (GCa) have limited treatment options, and alternative treatment approaches are necessary to improve their clinical outcomes. Because fibrin is abundant in gastric tumors but not in healthy tissues, we hypothesized that fibrin could be used as a high-concentration depot for a high-energy beta-emitting cytotoxic radiopharmaceutical delivered to tumor cells. We showed that fibrin is present in 64 to 75% of primary gastric tumors and 50 to 100% of metastatic gastric adenocarcinoma cores. First-in-human Cu-FBP8 fibrin-targeted positron emission tomography (PET) imaging in seven patients with gastric or gastroesophageal junction cancer showed high probe uptake in all target lesions with tumor-to-background (muscle) uptake ratios of 9.9 ± 6.6 in primary ( = 7) and 11.2 ± 6.6 in metastatic ( = 45) tumors. Using two mouse models of human GCa, one fibrin-high (SNU-16) and one fibrin-low (NCI-N87), we showed that PET imaging with a related fibrin-specific peptide, CM500, labeled with copper-64 (Cu-CM500) specifically bound to and precisely quantified tumor fibrin in both models. We then labeled the fibrin-specific peptide CM600 with yttrium-90 and showed that Y-CM600 effectively decreased tumor growth in these mouse models. Mice carrying fibrin-high SNU-16 tumors experienced tumor growth inhibition and prolonged survival in response to either a single high dosage or fractionated lower dosage of Y-CM600, whereas mice carrying fibrin-low NCI-N87 tumors experienced prolonged survival in response to a fractionated lower dosage of Y-CM600. These results lay the foundation for a fibrin-targeted theranostic that may expand options for patients with advanced GCa.
晚期胃癌（GCa）患者的治疗选择有限，因此需要采用替代治疗方法来改善其临床结局。由于纤维蛋白在胃肿瘤中含量丰富，而在健康组织中不存在，我们推测纤维蛋白可用作高浓度储存库，用于向肿瘤细胞递送发射高能β射线的细胞毒性放射性药物。我们发现，64%至75%的原发性胃肿瘤和50%至100%的转移性胃腺癌核心中存在纤维蛋白。对7例胃癌或胃食管交界癌患者进行的首例人体铜-纤维蛋白结合蛋白8（Cu-FBP8）纤维蛋白靶向正电子发射断层扫描（PET）成像显示，所有靶病变均有高探针摄取，原发性肿瘤（n = 7）的肿瘤与背景（肌肉）摄取比为9.9±6.6，转移性肿瘤（n = 45）为11.2±6.6。使用两种人GCa小鼠模型，一种纤维蛋白含量高（SNU-16），一种纤维蛋白含量低（NCI-N87），我们发现，用铜-64（Cu-CM500）标记的相关纤维蛋白特异性肽CM500进行PET成像，在两种模型中均能特异性结合并精确量化肿瘤纤维蛋白。然后，我们用钇-90标记纤维蛋白特异性肽CM600，结果显示Y-CM600在这些小鼠模型中有效抑制了肿瘤生长。携带纤维蛋白含量高的SNU-16肿瘤的小鼠，无论是单次高剂量还是分次低剂量的Y-CM600，均出现肿瘤生长抑制并延长了生存期，而携带纤维蛋白含量低的NCI-N87肿瘤的小鼠，分次低剂量的Y-CM600使其生存期延长。这些结果为纤维蛋白靶向治疗诊断奠定了基础，可能会为晚期GCa患者拓展治疗选择。
