New Industry Creation Hatchery Center, Tohoku University.
Department of Vascular Biology, Institute of Development, Aging, and Cancer, Tohoku University.
Tohoku J Exp Med. 2024 Mar 12;262(3):163-171. doi: 10.1620/tjem.2023.J109. Epub 2024 Jan 12.
As pancreatic ductal adenocarcinoma (PDAC) is extremely malignant and refractory, therapeutic options for this cancer are anticipated worldwide. We isolated vasohihibin-2 (VASH2) and observed its overexpression in various types of cancer. We then noticed that upregulated expression of VASH2 in patients with PDAC resulted in a conspicuous reduction in the postoperative survival period and further revealed that the abrogation of Vash2 expression in pancreatic cancer cells inhibited its growth and metastasis and augmented tumor infiltration of CD8 cells in the mouse model. We developed VASH2-targeting therapies, 2',4'-BNA-based antisense oligonucleotide targeting VASH2 (VASH2-ASO) as a nucleotide-based therapy, and VASH2-peptide vaccine as an antibody-based therapy. We also showed that the VASH2-peptide vaccine inhibited PDAC metastasis in an orthotopic mouse model. Here, we expanded our analysis of the efficacy of VASH2-targeting therapies for PDAC. VASH2-ASO treatment inhibited the growth of primary tumors by reducing tumor angiogenesis, normalizing tumor vessels, preventing ascites accumulation and distant metastasis to the liver and lungs, and augmenting the infiltration of CD8 cells in metastatic tumors. VASH2-peptide vaccine did not affect the infiltration of CD8 cells into tumors. The present study revealed that VASH2-targeting therapies are promising options for the treatment of PDAC. VASH2-ASO therapy can be administered at any stage of PDAC. Because of the increase of CD8 cell infiltration, the combination therapy with immune checkpoint inhibitors may be an attractive option. The VASH2-peptide vaccine therapy may be useful for preventing metastasis and/or recurrence after successful initial treatment.
由于胰腺导管腺癌 (PDAC) 具有极高的恶性和难治性，因此全球都在期待针对这种癌症的治疗选择。我们分离了血管抑制素-2 (VASH2)，并观察到其在各种类型的癌症中过度表达。然后我们注意到，PDAC 患者中 VASH2 的上调表达导致术后生存期明显缩短，进一步表明在胰腺癌细胞中敲低 Vash2 表达可抑制其生长和转移，并增加肿瘤浸润的 CD8 细胞。我们开发了针对 VASH2 的治疗方法，包括针对 VASH2 的 2'，4'-BNA 反义寡核苷酸 (VASH2-ASO) 作为核苷酸疗法，以及 VASH2 肽疫苗作为抗体疗法。我们还表明，VASH2 肽疫苗可抑制原位小鼠模型中的 PDAC 转移。在这里，我们扩展了对 VASH2 靶向治疗 PDAC 疗效的分析。VASH2-ASO 治疗通过减少肿瘤血管生成、使肿瘤血管正常化、防止腹水积聚以及防止肝和肺的远处转移，从而抑制原发肿瘤的生长，并增加转移瘤中 CD8 细胞的浸润。VASH2 肽疫苗不会影响 CD8 细胞浸润到肿瘤中。本研究表明，针对 VASH2 的治疗方法是治疗 PDAC 的有前途的选择。VASH2-ASO 治疗可在 PDAC 的任何阶段进行。由于 CD8 细胞浸润增加，与免疫检查点抑制剂的联合治疗可能是一种有吸引力的选择。VASH2 肽疫苗治疗可能有助于预防初始治疗成功后的转移和/或复发。
