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

项目摘要 狗中自然发生的骨肉瘤已被提出作为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，因为它是在完全 完整的免疫系统，并显示出与人类疾病相似的临床进展。此外，委员会认为， 犬骨肉瘤是一种自然发生的异质性疾病， 组织病理学、免疫学和人类疾病的基因组复杂性。尽管承诺 狗模型，这种模型的真正翻译潜力仍然未经证实，重要的物种 在传统的预防性治疗设计中， 专注狗试验优化犬骨肉瘤试验的设计和翻译影响 今后，该提案旨在共同确定这种疾病自然结果的广度和范围 深入表征肿瘤微环境和免疫景观。为了实现这些目标， 我们提出了以下两个目标：1）确定自然疾病进展和结果， 同期前瞻性入组的因自然发生的 骨肉瘤，和2）通知最佳设计，并建立生物学为基础的结果评估， 转化性犬骨肉瘤研究。这项工作将招收客户拥有的狗与自然发生的 骨肉瘤通过NCI比较肿瘤学试验联盟（COTC），一个完善的试验 兽医学术机构网络。除了治疗犬的主要临床结局指标外， 仅通过手术，深入表征肿瘤微环境和免疫景观将使我们能够 更好地了解固有生物学和化疗耐药性的影响，确定免疫系统的作用， 系统在疾病的自然进展，并比较分子和免疫签名之间的前， 现有的人类和犬骨肉瘤数据集。因此，该犬试验与相关生物标记物配对 研究的目的是通过确保未来的骨肉瘤模型的应用， 狗试验可以最佳地设计为人类患者的利益提供可靠的信息， 耐化疗的骨肉瘤

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.