Defining the role of core binding factor protein interactions in osteosarcoma

7.项目摘要/摘要 骨肉瘤(OS)是人类最常见的原发骨肿瘤，高达30% 用目前的多模式治疗，确诊的患者将无法存活5年。这种高级别肿瘤是最常见的 影响青少年和年轻人，通常需要手术、化疗，在某些情况下还需要放射治疗 心理治疗。在过去的30年里，生存时间没有任何改善，新的治疗形式是 迫切需要改善这些患者的预后。 矮小相关转录因子2(RUNX2)和核心结合因子β(CbFβ)是 异二聚体转录因子复合体参与有组织的骨骼发育。他们的正常活动 在OS以及其他癌症中调节失调，而且它们都与发育和 人类癌症的进展。本项目旨在确定这两者之间互动的重要性 研究OS恶性表型的蛋白质，并利用这些信息发现新的治疗靶点。这 通过使用CBFβ的变构抑制剂来阻止RUNX2结合并破坏RUNX2 转录复合体。该项目的具体目标将1)决定CBFβ-RUNX2的重要性 骨肉瘤恶性表型的相互作用，以及2)确定导致骨肉瘤恶性表型的分子机制 阻断脑血流量β-RUNX2相互作用，从而产生抗肿瘤效应。体外检测和体外检测相结合 纳入患者来源的异种移植小鼠OS模型将有助于确定CBFβ-RUNX2是如何介导的 OS细胞的存活和扩散。 机械学研究将被用来确定在促进 恶性表型由CBFβ-RUNX2相互作用介导。转录组学和蛋白质组学将 在抑制剂治疗后执行，这些数据集将被整合和分析，以揭示新的 进一步研究的治疗机会。在本方案中使用了一种新的犬类PDX OS模型 将有助于提供所需的验证，以证明未来在临床前模型中对这些发现的研究是合理的 自发发生的OS。 这些研究将通过提供以下方面的专门知识来指导Luke Wittenburg博士的职业发展 先进的分子技术、生物信息学和“组学”数据集的整合，以及先进的小鼠 人类癌症的模型。该项目将在合作范围内进行，以“一药”为中心 环境在加州大学戴维斯分校的国际知名专家的指导下 他们各自的领域是：陈新斌博士、C·泰特斯·布朗博士和余明明博士。这将使维滕伯格博士 实现他的职业目标，成为一名成功的独立研究人员，并在校外活动中具有竞争力 资助和一个富有成效和影响力的发展癌症治疗研究计划的基石。

7. Project Summary/Abstract Osteosarcoma (OS) is the most common primary bone neoplasm in people and up to 30% of those diagnosed will not survive 5 years with current, multimodal therapy. This high-grade tumor most frequently affects adolescents and young adults, often requiring surgery, chemotherapy and, in some cases, radiation therapy. With no improvements in survival times made over the past 30 years, novel forms of therapy are desperately needed to improve outcomes for these patients. Runt-related transcription factor 2 (RUNX2) and core binding factor beta (CBFβ) are members of a heterodimeric transcription factor complex involved in organized skeletal development. Their normal activities are dysregulated in OS, as well as in other cancers, and they have both been implicated in development and progression of human cancers. This project aims to identify the importance of the interaction between these two proteins for the malignant phenotype of OS, and use this information to uncover novel therapeutic targets. This will be accomplished through the use of allosteric inhibitors of CBFβ that prevent RUNX2 binding and disrupt the transcriptional complex. The Specific Aims of this project will 1) Determine the importance of the CBFβ-RUNX2 interaction for the malignant phenotype of osteosarcoma, and 2) Identify molecular mechanisms resulting from disruption of the CBFβ-RUNX2 interaction that induce an anti-tumor effect. A combination of in vitro assays and incorporation of patient-derived xenograft murine models of OS will help to identify how CBFβ-RUNX2 mediates OS cell survival and dissemination. Mechanistic studies will be used to identify the critical genes and pathways that are important in promoting the malignant phenotype and are mediated by CBFβ-RUNX2interaction. Transcriptomics and proteomics will be performed following inhibitor treatment and these data sets will be integrated and analyzed to uncover novel therapeutic opportunities for further investigation. The use of a novel canine PDX model of OS in this proposal will help provide the validation needed to justify future investigations of these findings in a pre-clinical model of spontaneously occurring OS. These studies will guide the career development of Dr. Luke Wittenburg by providing expertise in advanced molecular techniques, bioinformatics and integration of “omics” data sets, and advanced murine models of human cancer. This project will be performed within the collaborative, “One Medicine” centered environment at the University of California, Davis under the mentorship of internationally renowned experts in their respective fields; Dr. Xinbin Chen, Dr. C. Titus Brown and Dr. Aiming Yu. This will position Dr. Wittenburg to attain his career objective of becoming a successful independent researcher who is competitive for extramural funding and a cornerstone of a productive and impactful developmental cancer therapeutics research program.