Clinical, molecular, and immune characterization of naturally occurring osteosarcoma in dogs

犬自然发生的骨肉瘤的临床、分子和免疫特征

• 批准号: 10717426
• 负责人: Robert B Rebhun
• 金额: $ 58.46万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10717426
• 关键词: Acceleration; Address; Adolescent; Alternative Therapies; Amputation; Biological Markers; Biology; Canis familiaris; Chemoresistance; Child; Client; Clinical; Clinical Trials; Comparative Study; Complex; Cytotoxic Chemotherapy; Data; Data Commons; Data Set; Deposition; Disease; Disease Outcome; Disease Progression; Enrollment; Ensure; Future; Genetic; Genomics; Human; Immune; Immune system; Immunologics; Institution; Knowledge; Long-Term Survivors; Minority; Modeling; Molecular; Molecular Abnormality; Molecular Biology; Molecular Profiling; Mus; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Outcome Assessment; Patients; Pattern; Pharmaceutical Preparations; Platinum; Population; Population Control; Positioning Attribute; Primary Neoplasm; Rare Diseases; Research; Resistance; Resources; Retrospective Studies; Role; Survival Rate; Work; canine model; chemotherapy; clinical outcome measures; cohort; companion animal; comparative; design; effective therapy; high risk; human disease; improved; improved outcome; insight; mouse model; novel therapeutics; oncology trial; osteosarcoma; pre-clinical; prospective; screening; species difference; standard of care; success; transcriptomics; translational impact; translational model; translational potential; trial design; tumor microenvironment; tumor-immune system interactions

PROJECT SUMMARY Naturally occurring osteosarcoma in dogs has been proposed as a promising translational platform to serve as an intermediary between mouse studies and human clinical trials because it develops in the presence of a fully intact immune system and demonstrates a similar clinical progression to the human disease. Furthermore, canine osteosarcoma is a naturally occurring, heterogenous disease that recapitulates the spectrum of histopathologic, immunologic, and genomic complexity of the disease in humans. However, despite the promise of the dog model, the true translational potential of this model remains unproven and important species differences in overall outcomes exist that are often not accounted for in the traditional design of translationally focused dog trials. To optimize the design and translational impact of canine osteosarcoma trials moving forward, this proposal seeks to establish the breadth and range of natural outcomes for this disease together with deep characterization of the tumor microenvironment and immune landscape. To attain these objectives, we propose the following two aims, 1) Determine natural disease progression and outcomes in a contemporaneous prospectively enrolled population of dogs treated surgically for naturally occurring osteosarcoma, and 2) Inform optimal design and establish biologically based outcome assessments for translational canine osteosarcoma studies. This work will enroll client-owned dogs with naturally occurring osteosarcoma through the NCI Comparative Oncology Trials Consortium (COTC), a well-established trials network of veterinary academic institutions. In addition to primary clinical outcome measures for dogs treated with surgery alone, deep characterization of the tumor microenvironment and immune landscape will allow us to better understand the impacts of inherent biology and chemotherapy resistance, define the role of the immune system in the natural progression of disease, and to compare molecular and immune signatures between pre- existing human and canine osteosarcoma datasets. Hence, this canine trial paired with correlative bio-marker studies are aimed to expand and improve the utility of the canine osteosarcoma model by ensuring that future dog trials can be optimally designed to provide reliable information for the benefit of human patients with chemotherapy resistant osteosarcoma.

项目摘要 狗的自然发生的骨肉瘤被认为是一个有前途的翻译平台 小鼠研究和人类临床试验之间的中介是因为它在完全存在的情况下发展 完整的免疫系统，并证明了与人类疾病的临床进展相似。此外， 犬骨肉瘤是一种天然存在的异质疾病，可概括 人类疾病的组织病理学，免疫学和基因组复杂性。但是，尽管有希望 在狗模型中，该模型的真正翻译潜力仍然未经证实和重要物种 在传统的翻译设计中，总体结果的差异通常不考虑 专注的狗试验。优化犬骨肉瘤试验的设计和翻译影响 向前看，该提议旨在共同建立这种疾病的自然结果的广度和范围 肿瘤微环境和免疫景观的深刻表征。为了实现这些目标， 我们提出以下两个目标，1）确定自然疾病的发展和结果 前瞻性地招收的狗的人口被外科手术治疗 骨肉瘤和2）为最佳设计提供信息，并建立基于生物学的结果评估 翻译犬骨肉瘤研究。这项工作将注册客户拥有的狗，天然发生 骨肉瘤通过NCI比较肿瘤学试验（COTC），这是一项良好的试验 兽医学院网络。除了治疗的狗的主要临床结局指标 仅凭手术，肿瘤微环境和免疫景观的深刻表征将使我们能够 更好地了解固有生物学和化学疗法抗性的影响，定义免疫的作用 疾病自然进展的系统，并比较前疾病的分子和免疫信号 现有的人类和犬骨肉瘤数据集。因此，这种犬试验与相关生物标记配对 研究的目的是通过确保未来来扩展和改善犬骨肉瘤模型的实用性 狗试验是最佳设计的，以提供可靠的信息，以使人类患者受益 耐化学疗法骨肉瘤。