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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：
10652384
负责人：
RANDALL J KIMPLE
金额：
$ 50.74万
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/10652384
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 Pharyngeal structure Primary Neoplasm Research 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 Use Effectiveness Wisconsin anticancer treatment cancer therapy cost expectation experience head and neck cancer patient human disease human model humanized mouse immune cell infiltrate implantation improved improved outcome innovation mouse model novel novel therapeutics 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.

项目简介: