St. Vincent's Institute, 9 Princes St, Fitzroy, VIC, 3065, Australia.
Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, VIC, 3065, Australia.
Curr Osteoporos Rep. 2019 Oct;17(5):343-352. doi: 10.1007/s11914-019-00534-w.
Osteosarcoma (OS) is the most common cancer of bone, yet is classified as a rare cancer. Treatment and outcomes for OS have not substantively changed in several decades. While the decoding of the OS genome greatly advanced the understanding of the mutational landscape of OS, immediately actionable therapeutic targets were not apparent. Here we describe recent preclinical models that can be leveraged to identify, test, and prioritize therapeutic candidates.
The generation of multiple high fidelity murine models of OS, the spontaneous disease that arises in pet dogs, and the establishment of a diverse collection of patient-derived OS xenografts provide a robust preclinical platform for OS. These models enable evidence to be accumulated across multiple stages of preclinical evaluation. Chemical and genetic screening has identified therapeutic targets, often demonstrating cross species activity. Clinical trials in both PDX models and in canine OS have effectively tested new therapies for prioritization. Improving clinical outcomes in OS has proven elusive. The integrated target discovery and testing possible through a cross species platform provides validation of a putative target and may enable the rigorous evaluation of new therapies in models where endpoints can be rapidly assessed.
骨肉瘤（OS）是最常见的骨癌，但被归类为罕见癌症。几十年来，OS 的治疗和预后并未实质性改变。尽管 OS 基因组的解码极大地推进了对 OS 突变景观的理解，但并没有明显的直接治疗靶点。在这里，我们描述了最近的临床前模型，可以利用这些模型来识别、测试和优先考虑治疗候选物。
多种高保真 OS 鼠模型的生成，即发生在宠物狗身上的自发性疾病，以及多样化的患者来源 OS 异种移植的建立，为 OS 提供了一个强大的临床前平台。这些模型使证据能够在多个临床前评估阶段积累。化学和遗传筛选已经确定了治疗靶点，这些靶点通常显示出跨物种的活性。在 PDX 模型和犬 OS 中的临床试验有效地测试了新疗法的优先级。提高 OS 的临床结果一直难以实现。通过跨物种平台进行的综合目标发现和测试为假定的目标提供了验证，并可能使新疗法在可以快速评估终点的模型中得到严格评估。
