Integrin-αvβ6 targeted peptide-toxin therapy in a novel αvβ6-expressing immunocompetent model of pancreatic cancer

IF 2.8 2区医学 Q2 GASTROENTEROLOGY & HEPATOLOGY Pancreatology Pub Date : 2024-02-24 DOI:10.1016/j.pan.2024.02.013

Nicholas F. Brown , Elizabeth R. Murray , Lauren C. Cutmore , Philip Howard , Luke Masterson , Francesca Zammarchi , John A. Hartley , Patrick H. van Berkel , John F. Marshall

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Abstract

Previously we reported that a novel αvβ6-specific peptide-drug conjugate (SG3299) could eliminate established human pancreatic ductal adenocarcinoma (PDAC) xenografts. However the development of effective therapies for PDAC, which is an essential need, must show efficacy in relevant immunocompetent animals. Previously we reported that the KPC mouse transgenic PDAC model that closely recapitulates most stages of development of human PDAC, unlike in humans, failed to express αvβ6 on their tumours or metastases. In this study we have taken the KPC-derived PDAC line TB32043 and engineered a variant line (TB32043mb6S2) that expresses mouse integrin αvβ6. We report that orthotopic implantation of the αvβ6 over-expressing TB32043mb6S2 cells promotes shorter overall survival and increase in metastases. Moreover, systemic treatment of mice with established TB32043mb6S2 tumours in the pancreas with SG2399 lived significantly longer (p < 0.001; mean OS 48d) compared with PBS or control SG3511 (mean OS 25.5d and 26d, respectively). Thus SG3299 is confirmed as a promising candidate therapeutic for the therapy of PDAC.

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在新型αvβ6表达免疫功能健全的胰腺癌模型中应用整合素-αvβ6靶向肽毒素疗法

我们以前曾报道过一种新型αvβ6特异性多肽-药物共轭物（SG3299）能消除已建立的人胰腺导管腺癌（PDAC）异种移植物。然而，开发治疗 PDAC 的有效疗法，必须在相关免疫功能健全的动物身上显示出疗效，这是一项基本需求。以前我们曾报道过，KPC 小鼠转基因 PDAC 模型能近似再现人类 PDAC 的大部分发展阶段，但与人类不同的是，该模型的肿瘤或转移灶未能表达 αvβ6。在这项研究中，我们采用了源自 KPC 的 PDAC 株系 TB32043，并设计了一种表达小鼠整合素 αvβ6 的变异株系（TB32043mb6S2）。我们报告说，αvβ6 过度表达的 TB32043mb6S2 细胞的正位植入会缩短总生存期并增加转移。此外，与 PBS 或对照组 SG3511（平均生存期分别为 25.5 天和 26 天）相比，用 SG2399 对胰腺中已形成 TB32043mb6S2 肿瘤的小鼠进行全身治疗，其生存期明显更长（p < 0.001；平均生存期 48 天）。因此，SG3299 被证实是治疗 PDAC 的一种有希望的候选疗法。

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来源期刊

Pancreatology 医学-胃肠肝病学

CiteScore

7.20

自引率

5.60%

发文量

194

审稿时长

44 days

期刊介绍： Pancreatology is the official journal of the International Association of Pancreatology (IAP), the European Pancreatic Club (EPC) and several national societies and study groups around the world. Dedicated to the understanding and treatment of exocrine as well as endocrine pancreatic disease, this multidisciplinary periodical publishes original basic, translational and clinical pancreatic research from a range of fields including gastroenterology, oncology, surgery, pharmacology, cellular and molecular biology as well as endocrinology, immunology and epidemiology. Readers can expect to gain new insights into pancreatic physiology and into the pathogenesis, diagnosis, therapeutic approaches and prognosis of pancreatic diseases. The journal features original articles, case reports, consensus guidelines and topical, cutting edge reviews, thus representing a source of valuable, novel information for clinical and basic researchers alike.