Transforming family dogs into a powerful and accessible model for human cancer

将家养狗转变为强大且易于使用的人类癌症模型

• 批准号: 9891974
• 负责人: Elinor Karlsson
• 金额: $ 65.37万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891974
• 关键词: Address; Benchmarking; Biological Models; Biopsy; Blood; Blood specimen; Canis familiaris; Catalogs; Chemical Exposure; Clinical; Clinical Research; Clinical Trials; Code; Collection; Community Clinical Oncology Program; Computer software; Computing Methodologies; DNA sequencing; Data; Development; Diagnosis; Diagnostic; Dog family; Environment; Evolution; Gene Mutation; Genes; Genetic; Genomics; Gold; Histologic; Histology; Human; Inherited; Institutes; Learning; Life Style; Longitudinal Studies; Malignant Neoplasms; Medical center; Medicine; Methods; Modeling; Molecular Profiling; Mutate; Mutation; Oncology; Operative Surgical Procedures; Pathway interactions; Patients; Pattern; Phenotype; Records; Reporting; Research; Research Design; Research Personnel; Resources; Risk; Sampling; Scientist; Silicones; Techniques; Technology; Testing; Therapeutic; Time; Translating; Treatment outcome; United States; Untranslated RNA; Veterinarians; analysis pipeline; anticancer research; base; blind; cancer genomics; cancer subtypes; cell free DNA; chemotherapy; citizen science; classifier algorithm; cohort; comparative; comparative genomics; driver mutation; exome; exome sequencing; experience; genetic risk factor; genome sequencing; genomic data; genomic platform; human data; human model; improved; liquid biopsy; minimally invasive; new technology; novel strategies; open source; precision medicine; predicting response; programs; response; smartphone Application; software development; supervised learning; targeted treatment; tool; translational cancer research; translational model; tumor; whole genome

ABSTRACT There is an unmet need for novel approaches to cancer research, including improved model systems. Pet dogs are among the most promising natural models for translational cancer research​. They share our environment and develop cancers with clear clinical, histological, and genomic similarities to human cancer. We propose to use new genomic technology and a direct-to-dog-owner approach to overcome existing limitations of the canine model. To accomplish this, we will use new liquid biopsy technology, which makes it possible to sequence ​tumor exomes in circulating cell-free DNA from a blood sample, and thus achieve deeper understanding of tumor genomics without invasive biopsies. The power of these minimally invasive sampling technologies is greatest in application to very large sets of clinical samples. Family dogs, whose environments are shared with humans and for which tumor genomics are similar to human cancers, offer an unparalleled model in which to assemble clinical sets of size sufficient both to confirm the relevance of known genetic pathways, and to identify new ones. We propose to combine the power of cell-free DNA sequencing, ​the enthusiasm of citizen-scientist pet owners, and the clinical experience of veterinarians. We will create a research portal for collection of information on diagnosis, treatment, and outcome for thousands of dogs with cancer, as well as their environment and lifestyle. W​e will also develop new computational methodologies to identify genomic similarities between canine and human cancers. Comparison of these canine and human mutational profiles will enable matching of canine cancer subtypes with human cancer subtypes based on genetic pathways, facilitating canine trials to advance human clinical studies. We aim to: Aim 1. ​Develop software to Identify canine models for human cancers using genomic data and comprehensive, histology-blind analysis approach. Aim 2. Develop and optimize ​cell-free DNA sampling and sequencing methods in dogs, including ultra-low-pass whole genome sequencing and whole exome sequencing. Aim 3. Implement a ​direct-to-dog-owner smartphone app to collect and validate detailed clinical, and environmental data, paired with blood samples, for thousands of dogs. By combining the power of genome sequencing and new liquid biopsy technology with the opportunity to collect large sets of samples from a species whose cancers are genomically reflective of those in humans, our project​ will​ transform​ the scale and scope of translational cancer research and precision medicine.

抽象的 对癌症研究的新方法（包括改进的模型系统）的需求尚未得到满足。宠物狗 是转化癌症研究最有前途的自然模型之一。他们分享我们的 环境并发展出与人类癌症具有明显临床、组织学和基因组相似性的癌症。 我们建议使用新的基因组技术和直接面向狗主人的方法来克服现有的 犬模型的局限性。 为了实现这一目标，我们将使用新的液体活检技术，这使得对肿瘤进行测序成为可能 血液样本中循环游离 DNA 中的外显子组，从而更深入地了解肿瘤 无需侵入性活检的基因组学。这些微创采样技术的力量是最大的 适用于非常大的临床样本集。家庭犬，其环境与人类共享 肿瘤基因组学与人类癌症相似，提供了一个无与伦比的模型来组装 临床组的规模足以确认已知遗传途径的相关性，并识别新的 那些。 我们建议将无细胞 DNA 测序的力量、公民科学家宠物主人的热情、 以及兽医的临床经验。我们将创建一个研究门户网站来收集相关信息 数千只患有癌症的狗的诊断、治疗和结果，以及它们的环境和 生活方式。我们还将开发新的计算方法来识别之间的基因组相似性 犬类和人类癌症。这些犬类和人类突变谱的比较将能够匹配 根据遗传途径将犬类癌症亚型与人类癌症亚型进行比较，促进犬类试验 推进人体临床研究。我们的目标是： 目标 1.​开发软件，利用基因组数据和识别人类癌症的犬类模型 全面的组织学盲分析方法。 目标 2. 开发和优化狗的无细胞 DNA 采样和测序方法，包括 超低通全基因组测序和全外显子组测序。 目标 3. 实施一个直接面向狗主人的智能手机应用程序来收集和验证详细的临床数据，以及 数千只狗的环境数据以及血液样本。 通过结合基因组测序和新液体活检技术的力量，有机会 从一个物种中收集大量样本，该物种的癌症在基因组上反映了人类的癌症，我们的 项目将改变转化癌症研究和精准医学的规模和范围。