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 64 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 ( n = 7) and 11.2 ± 6.6 in metastatic ( n = 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 ( 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 90 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 90 Y-CM600, whereas mice carrying fibrin-low NCI-N87 tumors experienced prolonged survival in response to a fractionated lower dosage of 90 Y-CM600. These results lay the foundation for a fibrin-targeted theranostic that may expand options for patients with advanced GCa.

中文翻译：

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用于胃癌的纤维蛋白靶向治疗诊断仪的开发


晚期胃癌 （GCa） 患者的治疗选择有限，需要替代治疗方法来改善其临床结果。由于纤维蛋白在胃肿瘤中含量丰富，但在健康组织中含量不高，我们假设纤维蛋白可以用作输送到肿瘤细胞的高能 β 发射细胞毒性放射性药物的高浓度贮库。我们发现纤维蛋白存在于 64% 至 75% 的原发性胃肿瘤和 50% 至 100% 的转移性胃腺癌核心中。7 例胃癌或胃食管交界处癌患者的首次人体 64 Cu-FBP8 纤维蛋白靶向正电子发射断层扫描 （PET） 成像显示，所有靶病变的探针摄取率均很高，原发性 （n = 7） 的肿瘤背景（肌肉）摄取比为 9.9 ± 6.6，转移性 （n = 45） 肿瘤为 11.2 ± 6.6。使用两个人 GCa 小鼠模型，一个高纤维蛋白 （SNU-16） 和一个低纤维蛋白 （NCI-N87），我们表明，使用相关纤维蛋白特异性肽 CM500 的 PET 成像，用铜 64 （ 64 Cu-CM500） 标记，特异性结合并精确量化两个模型中的肿瘤纤维蛋白。然后，我们用钇 90 标记纤维蛋白特异性肽 CM600，并表明 90 个 Y-CM600 有效降低了这些小鼠模型中的肿瘤生长。携带纤维蛋白高 SNU-16 肿瘤的小鼠在单次高剂量或分级低剂量 90 Y-CM600 后经历了肿瘤生长抑制和延长生存期，而携带纤维蛋白低 NCI-N87 肿瘤的小鼠在响应 90 Y-CM600 的分级低剂量后经历了延长的生存期。这些结果为纤维蛋白靶向治疗诊断学奠定了基础，这可能会扩大晚期 GCa 患者的选择。