Improving the translational value of head and neck cancer patient-in-mouse models

项目摘要： 患者来源的模型系统通常用于研究肿瘤生物学和测试用于治疗肿瘤的新疗法。 头颈癌这些模型是使用来源于手术标本的患者肿瘤建立的 并且通常植入小鼠的皮下组织中。几乎没有数据可以支持 我们在最初处理肿瘤样本时做出的决定，最重要的是，这些决定是如何做出的， 影响后续研究的结果。我们的长期目标是改善头颈癌的预后 患者使用有效的、预测性的和良好表征的模型系统。本申请的总体目标 通过理解我们所做选择的影响， 当我们建立他们。通过结合创新的方法来研究癌症演变， 评估肿瘤生物学和治疗反应，我们希望最终提高研究的相关性 利用这些哺乳动物模型来改善对人类病人的护理。我们的中心假设是， 用于建立患者来源的异种移植物的方法对其作为转化的相关性具有关键影响 模型 为了实现我们的目标，我们提出了三个目标。在目标1中，我们将确定异位与 原位移植对肿瘤生物学的影响，患者来源的动物模型如何随着肿瘤的增加而变化， 在动物中的传代，以及这些因素如何影响肿瘤的演变。在目标2中，我们将测试 通过使用患者来源的异种移植物，患者来源的模型和患者之间的反应， 一项正在进行的（单独供资的）“机会之窗”试验，并将评估 标准治疗随着时间的推移。在Aim 3中，我们将使用一种创新的人源化小鼠模型， 威斯康星州评估肿瘤和免疫系统之间的进化相互作用，了解是否 这些新的小鼠复制了在人类癌症或同基因HNC模型中看到的肿瘤/免疫界面， 并研究对免疫治疗的反应如何复制患者中所见。总之，这些 研究将为我们如何优化使用人类头部的小鼠模型提供令人信服的证据， 颈癌该项目的完成将提供强有力的证据，说明和完善以下方面的最佳做法： 患者来源的头颈癌异种移植动物模型的转化应用。

Project Abstract: Patient-derived model systems are commonly used to study tumor biology and test novel treatments for head and neck cancer. These models are established using patient tumors sourced from surgical specimens and typically implanted into the subcutaneous tissue of the mouse. There is little data available to support the decisions we make during the initial handling of the tumor samples and, most importantly, how these decisions impact the results of subsequent studies. Our long-term goal is to improve outcomes for head and neck cancer patients using valid, predictive, and well characterized model systems. The overall objective of this application is to improve our use of these mammalian model systems by understanding the impact of choices we make when we establish them. By combining innovative approaches to study cancer evolution with rigorous assessment of tumor biology and therapy response we hope to ultimately improve the relevance of studies using these mammalian models to improve the care of human patients. Our central hypothesis is that the approach used to establish patient-derived xenografts has a critical impact on their relevance as translational models. To achieve our goals, we proposed three aims. In Aim 1, we will determine the role of heterotopic vs. orthotopic implantation on the biology of the tumor, how patient-derived animal models change with increasing passage in animals, and how these factors impact tumor evolution. In Aim 2, we will test the concordance of response between patient derived models and patients by using patient derived xenografts established as part of an ongoing (and separately funded) window-of-opportunity trial and will assess consistency in response to standard treatments over time. In Aim 3, we will use an innovative humanized mouse model developed at Wisconsin to assess the evolutionary interplay between the tumor and immune system, understand whether these novel mice replicate the tumor/immune interface seen in human cancers or in syngeneic HNC models, and investigate how well the response to immunotherapy replicates that seen in patients. In summary, these studies will provide compelling evidence for how to optimize our use of mouse models of human head and neck cancer. Completion of this project will provide robust evidence delineating and refining best practices for the translational use of patient derived xenograft animal models of head and neck cancer.