Ferdous Khandoker Usran, Tesfay Mulu Z, Cios Aleksandra, Shelton Randal S, Hartupee Conner, Urbaniak Alicja, Chamcheu Jean Christopher, Mavros Michail N, Giorgakis Emmanouil, Mustafa Bahaa, Simoes Camila C, Miousse Isabelle R, Basnakian Alexei G, Moaven Omeed, Post Steven R, Cannon Martin J, Kelly Thomas, Nagalo Bolni Marius
Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Biomedicines. 2024 Jul 18;12(7):1596. doi: 10.3390/biomedicines12071596.
About one-fourth of patients with pancreatic ductal adenocarcinoma (PDAC) are categorized as borderline resectable (BR) or locally advanced (LA). Chemotherapy and radiation therapy have not yielded the anticipated outcomes in curing patients with BR/LA PDAC. The surgical resection of these tumors presents challenges owing to the unpredictability of the resection margin, involvement of vasculature with the tumor, the likelihood of occult metastasis, a higher ratio of positive lymph nodes, and the relatively larger size of tumor nodules. Oncolytic virotherapy has shown promising activity in preclinical PDAC models. Unfortunately, the desmoplastic stroma within the PDAC tumor microenvironment establishes a barrier, hindering the infiltration of oncolytic viruses and various therapeutic drugs-such as antibodies, adoptive cell therapy agents, and chemotherapeutic agents-in reaching the tumor site. Recently, a growing emphasis has been placed on targeting major acellular components of tumor stroma, such as hyaluronic acid and collagen, to enhance drug penetration. Oncolytic viruses can be engineered to express proteolytic enzymes that cleave hyaluronic acid and collagen into smaller polypeptides, thereby softening the desmoplastic stroma, ultimately leading to increased viral distribution along with increased oncolysis and subsequent tumor size regression. This approach may offer new possibilities to improve the resectability of patients diagnosed with BR and LA PDAC.
约四分之一的胰腺导管腺癌（PDAC）患者被归类为边缘可切除（BR）或局部晚期（LA）。化疗和放疗在治愈BR/LA PDAC患者方面尚未取得预期效果。由于切除边缘的不可预测性、肿瘤对脉管系统的侵犯、隐匿转移的可能性、阳性淋巴结比例较高以及肿瘤结节相对较大，这些肿瘤的手术切除面临挑战。溶瘤病毒疗法在临床前PDAC模型中已显示出有前景的活性。不幸的是，PDAC肿瘤微环境中的促纤维增生性基质形成了一道屏障，阻碍溶瘤病毒和各种治疗药物（如抗体、过继性细胞治疗药物和化疗药物）渗透到肿瘤部位。最近，越来越强调靶向肿瘤基质的主要无细胞成分，如透明质酸和胶原蛋白，以增强药物渗透。可以对溶瘤病毒进行工程改造，使其表达能将透明质酸和胶原蛋白切割成较小多肽的蛋白水解酶，从而软化促纤维增生性基质，最终导致病毒分布增加，同时溶瘤作用增强，随后肿瘤大小缩小。这种方法可能为提高诊断为BR和LA PDAC患者的可切除性提供新的可能性。
