Determining the efficacy and safety of cancer chemotherapeutics for cholangiocarcinoma (CCA) using Human Precision Cut Tissue Slices (hPCTS).

使用人体精密切割组织切片 (hPCTS) 确定胆管癌 (CCA) 癌症化疗的有效性和安全性。

• 批准号: NC/W001020/1
• 负责人: Laura Randle
• 金额: $ 9.44万
• 依托单位: Liverpool John Moores University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=NC%2FW001020%2F1
• 关键词: Determining; efficacy; safety; cancer; chemotherapeutics

Cholangiocarcinoma (CCA) is a bile duct cancer and one of the worst outcome human malignancies. Late-stage diagnosis and limited therapeutic options means that survival rates are low and it is a cancer of unmet need.Mouse models of hepatobiliary cancer have been generated to unravel the molecular mechanisms that drive this disease. Genetic mutations can be induced chemically or virally to promote tumour formation, alternatively key pathways that drive malignant transformation can be disrupted or 'knocked out' , alongside xenograft models whereby tumour cells are implanted into immunodeficient mice. However, in vivo approaches are costly, time-consuming and raise ethical concerns. Therefore, in vitro alternatives to investigate bile duct cancer progression are urgently needed.Precision cut tumour slices are three-dimensional structures of hepatobiliary cells that can be cultured ex vivo. They recapitulate critical aspects of the hepatobiliary cancer biology and, crucially retain the original tumour microenvironment. In this proposal, we propose to implement the use of precision cut tissue slices derived from human tumour tissue (hPCTS) in our lab to study the molecular mechanisms driving disease progression. Our scientific goal is to establish and validate tumour slice viability in the lab and maintenance of liver and bile duct functionality over time and to ensure that the tumour mutations are retained in culture. We will then assess the ability of hPCTS CCA to respond to Gemcitabine and Cisplatin, anti-cancer drugs that are standard care for bile duct cancer. We will identify invading immune cells and the tumour slice's ability to respond to cancer immunotherapies. Finally, we will confirm their clinical relevance by exposing hPCTS to a panel of molecular targeted anti-cancer drugs to determine their ability to stop tumour growth.Overall, we anticipate that our approach will offer a biologically relevant in vitro model to understand bile duct cancer mutations which can be targeted with anti-cancer drugs, thereby replacing the use of mice to study vital biological aspects of this disease.

胆管癌（CCA）是一种胆管癌，也是预后最差的人类恶性肿瘤之一。晚期诊断和有限的治疗选择意味着生存率很低，而且它是一种未满足需求的癌症。肝胆癌的小鼠模型已经建立，以揭示驱动这种疾病的分子机制。可以通过化学或病毒诱导基因突变以促进肿瘤形成，或者可以破坏或“敲除”驱动恶性转化的关键途径，以及将肿瘤细胞植入免疫缺陷小鼠的异种移植模型。然而，体内方法成本高昂、耗时且引发伦理问题。因此，迫切需要体外替代方法来研究胆管癌的进展。精密切割的肿瘤切片是可以离体培养的肝胆细胞的三维结构。它们概括了肝胆癌生物学的关键方面，并且至关重要的是保留了原始的肿瘤微环境。在本提案中，我们建议在我们的实验室中使用源自人类肿瘤组织（hPCTS）的精密切割组织切片来研究驱动疾病进展的分子机制。我们的科学目标是在实验室中建立和验证肿瘤切片的活力以及肝脏和胆管功能随时间的维持，并确保肿瘤突变保留在培养物中。然后，我们将评估 hPCTS CCA 对吉西他滨和顺铂（胆管癌标准治疗抗癌药物）的反应能力。我们将识别入侵的免疫细胞和肿瘤切片对癌症免疫疗法做出反应的能力。最后，我们将通过将 hPCTS 暴露于一组分子靶向抗癌药物以确定其阻止肿瘤生长的能力来确认其临床相关性。总体而言，我们预计我们的方法将提供生物学相关的体外模型来了解可以用抗癌药物靶向的胆管癌突变，从而取代使用小鼠来研究该疾病的重要生物学方面。