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

项目摘要： 患者衍生的模型系统通常用于研究肿瘤生物学和测试新的治疗方法 头颈癌。这些模型是使用来自手术标本的患者肿瘤建立的。 通常植入小鼠的皮下组织。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部癌症的治疗结果 患者使用有效的、可预测的和具有良好特征的模型系统。本应用程序的总体目标是 是通过了解我们做出的选择的影响来改进我们对这些哺乳动物模型系统的使用 当我们建立起它们的时候。通过将研究癌症进化的创新方法与严格的 对肿瘤生物学和治疗反应的评估我们希望最终提高研究的相关性 使用这些哺乳动物模型来改善对人类患者的护理。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它们作为翻译的相关性具有关键影响 模特们。 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年龄的增加而变化 动物传代，以及这些因素如何影响肿瘤进化。在目标2中，我们将测试 部分建立的患者来源异种移植物在患者来源模型和患者之间的反应 正在进行的(和单独资助的)机会窗试验，并将评估一致性，以应对 随着时间的推移，标准治疗方法。在目标3中，我们将使用在 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 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， 并调查免疫治疗的反应在多大程度上复制了患者的反应。总而言之，这些 研究将提供令人信服的证据，说明如何优化使用人类头部和大脑的老鼠模型 颈癌。该项目的完成将提供强有力的证据，描绘和完善以下最佳做法 头颈部癌患者来源的异种移植动物模型的翻译应用。

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.