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.

项目总结 狗自然发生的骨肉瘤被认为是一种很有前途的翻译平台，可以作为 小鼠研究和人类临床试验之间的中介，因为它是在完全 完整的免疫系统，并表现出与人类疾病相似的临床进展。此外， 犬骨肉瘤是一种自然发生的异质性疾病，它概括了 人类疾病的组织病理学、免疫学和基因组学的复杂性。然而，尽管有承诺， 在狗模型中，这种模型的真正翻译潜力仍然是未经证实的和重要的物种 总体结果存在差异，这在传统的翻译设计中往往没有考虑到 专心致志的狗试验。优化犬骨肉瘤试验MOVING的设计和翻译影响 展望未来，这项提案寻求共同确定这种疾病的自然后果的广度和范围 具有对肿瘤微环境和免疫格局的深刻表征。为了实现这些目标， 我们提出了以下两个目标：1)确定自然疾病的进展和结果 同期预期登记的因自然发生而接受手术治疗的狗的数量 骨肉瘤，以及2)为最佳设计提供信息并建立基于生物学的结果评估 转译犬骨肉瘤研究。这项工作将登记客户拥有的狗与自然发生 骨肉瘤通过NCI肿瘤学比较试验联盟(COTC)进行，这是一项久负盛名的试验 兽医学术机构网络。除了对接受治疗的狗的主要临床结果衡量之外 仅通过手术，深入描述肿瘤微环境和免疫状况将使我们能够 更好地了解固有生物学和化疗耐药性的影响，确定免疫的作用 系统在疾病的自然发展中的作用，并比较前两者之间的分子和免疫特征 现有的人类和犬类骨肉瘤数据集。因此，这项犬类试验与相关的生物标记配对 研究的目的是扩大和提高犬骨肉瘤模型的实用性，以确保未来 狗的试验可以被优化设计，为人类患者的利益提供可靠的信息 化疗耐药的骨肉瘤。