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

提高头颈癌小鼠模型的转化价值

基本信息

批准号：
10298211
负责人：
RANDALL J KIMPLE
金额：
$ 52.1万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10298211
关键词：
Address Affect Age Animal Experimentation Animal Model Animals Biological Biological Models Biology Cancer Model Caring Cetuximab Clinical Clinical Trials DNA sequencing Data Decision Making Evolution Funding Generations Genetic Genetic Variation Goals HPV-negative head and neck cancer Head and Neck Cancer Histologic Human Human Biology Human Papillomavirus Immune Immune system Immunocompetent Immunocompromised Host Immunotherapy Implant In Situ In Vitro Longevity Malignant Neoplasms Methodology Methods Modeling Molecular Mus Nose Operative Surgical Procedures Oral Organoids Outcome Pathway interactions Patient Care Patients Primary Neoplasm Research Research Proposals Resistance Role Sampling Scientist Serial Passage Signal Pathway Site Skin Source Specimen Squamous Epithelium Squamous cell carcinoma Subcutaneous Tissue Testing Therapeutic Studies Time Translating Tumor Biology Tumor-infiltrating immune cells Use Effectiveness Wisconsin anticancer treatment base cancer therapy cost expectation experience head and neck cancer patient human disease human model humanized mouse implantation improved improved outcome innovation mouse model novel novel therapeutics overtreatment patient derived xenograft model patient response pre-clinical pre-clinical research prevent response single-cell RNA sequencing standard care subcutaneous targeted treatment therapy resistant translational model treatment response tumor tumor microenvironment tumor-immune system interactions

项目摘要

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.

项目摘要：源自患者的模型系统通常用于研究肿瘤生物学和测试新疗法头颈癌。这些模型是使用来自手术标本的患者肿瘤建立的通常被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期间做出的决定，以及最重要的是，这些决定如何影响后续的研究结果。我们的长期目标是改善头颈癌的治疗结果患者使用有效的、预测性的、特征良好的模型系统。该应用程序的总体目标是通过了解我们所做选择的影响来改善我们对这些哺乳动物模型系统的使用当我们建立它们时。通过将研究癌症进化的创新方法与严格的方法相结合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使用这些哺乳动物模型来改善人类患者的护理。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其作为转化的相关性具有至关重要的影响模型。为了实现我们的目标，我们提出了三个目标。在目标 1 中，我们将确定异位与异位的作用。原位植入对肿瘤生物学的影响，源自患者的动物模型如何随着肿瘤细胞数量的增加而变化动物体内的传代，以及这些因素如何影响肿瘤的进化。在目标 2 中，我们将测试以下内容的一致性通过使用作为一部分建立的患者衍生异种移植物，患者衍生模型和患者之间的反应正在进行的（单独资助的）机会之窗试验，并将评估响应的一致性随着时间的推移进行标准治疗。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，了解是否这些新型小鼠复制了人类癌症或同基因 HNC 模型中看到的肿瘤/免疫界面，并研究免疫疗法的反应在患者身上的复制效果如何。综上所述，这些研究将为如何优化我们对人类头部小鼠模型的使用提供令人信服的证据颈部癌症。该项目的完成将为描述和完善最佳实践提供有力的证据源自患者的头颈癌异种移植动物模型的转化应用。