Defining the role of core binding factor protein interactions in osteosarcoma

7.项目概要/摘要 骨肉瘤（OS）是人类最常见的原发性骨肿瘤， 确诊的患者在目前的多模式治疗下无法存活5年。这种高级别肿瘤最常发生在 影响青少年和年轻人，通常需要手术，化疗，在某些情况下，放射治疗 疗法由于在过去的30年里生存时间没有改善，新的治疗形式正在出现。 迫切需要改善这些患者的治疗效果。 Runt相关转录因子2（RUNX 2）和核心结合因子β（CBFβ）是一个转录因子家族的成员。 参与有组织骨骼发育的异二聚体转录因子复合物。正常活动 在OS以及其他癌症中失调，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的相互作用的重要性 的恶性表型的蛋白质，并使用这些信息来发现新的治疗靶点。这 将通过使用CBFβ的别构抑制剂来实现，该别构抑制剂阻止RUNX 2结合并破坏 转录复合体本项目的具体目标是：1）确定CBFβ-RUNX的重要性2 骨肉瘤恶性表型的相互作用，和2）确定导致骨肉瘤恶性表型的分子机制， CBFβ-RUNX 2相互作用的破坏诱导抗肿瘤作用。体外测定和 合并患者来源的OS异种移植小鼠模型将有助于确定CBFβ-RUNX 2如何介导 OS细胞存活和扩散。 机制研究将用于确定关键基因和途径，这是重要的促进 CBFβ-RUNX 2相互作用介导的恶性表型。转录组学和蛋白质组学将 在抑制剂治疗后进行，这些数据集将被整合和分析，以发现新的 治疗的机会，以进一步研究。在该提议中使用了一种新的犬PDX OS模型 将有助于提供必要的验证，以证明未来在临床前模型中对这些发现的研究是合理的。 自发性OS。 这些研究将通过提供以下专业知识来指导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， 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; Xinbin Chen博士，C.泰特斯·布朗和余艾明博士这将使维滕伯格博士 实现他的职业目标，成为一个成功的独立研究人员谁是竞争的校外 资金和一个富有成效的和有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.