Gopinathan Aarthi, Morton Jennifer P, Jodrell Duncan I, Sansom Owen J
Cancer Research UK Cambridge Institute, University of Cambridge, Robinson Way, Cambridge, CB2 0RE, UK
Cancer Research UK Beatson Institute, Glasgow, G61 1BD, UK.
Dis Model Mech. 2015 Oct 1;8(10):1185-200. doi: 10.1242/dmm.021055.
Pancreatic ductal adenocarcinoma is the most common form of pancreatic tumour, with a very limited survival rate and currently no available disease-modifying treatments. Despite recent advances in the production of genetically engineered mouse models (GEMMs), the development of new therapies for pancreatic cancer is still hampered by a lack of reliable and predictive preclinical animal models for this disease. Preclinical models are vitally important for assessing therapies in the first stages of the drug development pipeline, prior to their transition to the clinical arena. GEMMs carry mutations in genes that are associated with specific human diseases and they can thus accurately mimic the genetic, phenotypic and physiological aspects of human pathologies. Here, we discuss different GEMMs of human pancreatic cancer, with a focus on the Lox-Stop-Lox (LSL)-Kras(G12D); LSL-Trp53(R172H); Pdx1-cre (KPC) model, one of the most widely used preclinical models for this disease. We describe its application in preclinical research, highlighting its advantages and disadvantages, its potential for predicting clinical outcomes in humans and the factors that can affect such outcomes, and, finally, future developments that could advance the discovery of new therapies for pancreatic cancer.
胰腺导管腺癌是最常见的胰腺肿瘤形式，生存率极低，目前尚无有效的疾病改善治疗方法。尽管基因工程小鼠模型（GEMMs）的构建取得了最新进展，但胰腺癌新疗法的开发仍因缺乏针对该疾病的可靠且可预测的临床前动物模型而受阻。临床前模型对于在药物研发流程的第一阶段评估疗法至关重要，然后才进入临床阶段。GEMMs在与特定人类疾病相关的基因中携带突变，因此能够准确模拟人类病理的遗传、表型和生理方面。在此，我们讨论人类胰腺癌的不同GEMMs，重点关注Lox-Stop-Lox（LSL）-Kras（G12D）；LSL-Trp53（R172H）；Pdx1-cre（KPC）模型，这是该疾病最广泛使用的临床前模型之一。我们描述了其在临床前研究中的应用，强调了其优缺点、预测人类临床结果的潜力以及可能影响此类结果的因素，最后阐述了可能推动胰腺癌新疗法发现的未来发展方向。
