Faculty of Health Sciences, University of Macau, Avenida de Universidade, Macau.
Histopathology Core, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Macau.
Eur J Pharm Sci. 2017 Dec 15;110:62-69. doi: 10.1016/j.ejps.2017.05.057. Epub 2017 May 26.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types of tumor amongst all human cancers due to late diagnosis and resistant to treatment with chemotherapy and radiation. Preclinical and clinical studies have revealed that ErbB family for example epidermal growth factor receptor (EGFR) is a validated molecular target for pancreatic cancer prevention and therapy. The ErbB signaling cascade is regulated by a member of the ADAM (a disintegrin and metalloprotease) family, namely ADAM17, by enzymatic cleavage of precursor ligands into soluble cytokines and growth factors. Mouse genetic studies have demonstrated that ADAM17 is required for PDAC development. In this study, we evaluated the anti-tumor effects of A9(B8) IgG - the first specific 'human and mouse cross-reactive' ADAM17 inhibitory antibody on pancreatic malignant transformation. We found that inhibition of ADAM17 with A9(B8) IgG efficiently suppressed the shedding of ADAM17 substrates both in vivo and in vitro. Furthermore, we demonstrated that administration of A9(B8) IgG significantly suppressed motility in human pancreatic cancer cells and also significantly delayed tumorigenesis in the Pdx1Cre;Kras;Trp53PDAC mouse model. Inhibition of ADAM17 with A9(B8) IgG particularly affected the progression of pre-invasive pancreatic lesions to advanced PDAC in mice. Taken together, the preclinical data presented here will provide a starting point for clinical applications of ADAM17 targeted therapy.
胰腺导管腺癌（PDAC）是人类癌症中最致命的肿瘤类型之一，其原因是诊断较晚且对化疗和放疗有耐药性。临床前和临床研究表明，表皮生长因子受体（EGFR）等 ErbB 家族是预防和治疗胰腺癌的有效分子靶点。ErbB 信号级联反应受 ADAM（解整合素和金属蛋白酶）家族成员 ADAM17 的调节，通过酶切将前体配体切割成可溶性细胞因子和生长因子。小鼠遗传学研究表明 ADAM17 是 PDAC 发展所必需的。在这项研究中，我们评估了 A9（B8）IgG 对胰腺恶性转化的抗肿瘤作用，A9（B8）IgG 是第一个特异性“人源和鼠源交叉反应”的 ADAM17 抑制性抗体。我们发现，用 A9（B8）IgG 抑制 ADAM17 能有效抑制体内和体外 ADAM17 底物的脱落。此外，我们证明 A9（B8）IgG 的给药能显著抑制人胰腺癌细胞的迁移，并显著延迟 Pdx1Cre；Kras；Trp53PDAC 小鼠模型中的肿瘤发生。用 A9（B8）IgG 抑制 ADAM17 特别影响了小鼠中前侵袭性胰腺病变向晚期 PDAC 的进展。综上所述，这里提出的临床前数据将为 ADAM17 靶向治疗的临床应用提供一个起点。
