The Center for Therapeutic Targeting of EWS-oncoproteins

项目总结：总体 本节与U54 CA231637家长奖相同。 该中心的主要科学重点是了解EWS-ETS的分子基础 驱动尤文肉瘤并探索新的治疗方法和改善治疗机制 患有这种侵袭性疾病的儿科患者的预后。分子翻译 将肉瘤的病理生理学理解为临床上有效的新药是一项复杂、有风险的工作 这一命题需要一支才华横溢、技能互补的个人团队共同努力。 这个小组带来了尤文肉瘤生物学和EWS-ETS癌蛋白、表观遗传学和 转录、结构生物学、计算生物学、化学生物学和药物开发 模型、临床前实验疗法和临床试验发展。中心机构是 对这项提议的成功至关重要。任何一个机构或个人都不能掌握 实现本提案目标所需的方法、技术和科学领域。我们有 被选为专注于了解尤因肉瘤的基本内部工作原理 转录回路，到与EWS-FLI1的直接蛋白质相互作用，到直接和即时 EWS-FLI1降解的影响。此外，这项提议的重点是目标。 识别和临床前验证是提出最佳治疗方案过程中的关键步骤 在诊所取得成功的机会。组装好的团队拥有所需的所有组件 为了成功。我们的中心包括杰出的基础癌症生物学家、化学家、计算生物学家、 还有翻译研究人员和五位儿科肿瘤学家。因此，建议的中心可以催化碱性 通过利用中心和我们的基础和临床研究人才进行发现和临床翻译 与外部学术和工业合作伙伴的紧密联系。

PROJECT SUMMARY: Overall This section is unchanged from the U54 CA231637 parent award. The primary scientific focus of this Center is to understand the molecular underpinnings of EWS-ETS driven Ewing sarcoma and to investigate novel treatments and therapeutic mechanisms to improve outcomes for pediatric patients with this aggressive disease. Translation of molecular understanding of sarcoma pathophysiology into effective new drugs in the clinic is a complex, risky proposition that requires the coordinated efforts of a talented team of individuals with complementary skills. This group brings expertise in Ewing sarcoma biology and the EWS-ETS oncoproteins, epigenetics and transcription, structural biology, computational biology, chemical biology and drug development, mouse models, preclinical experimental therapeutics, and clinical trials development. A Center mechanism is essential to the success of this proposal. No one institution nor individual can bring mastery of the diversity of approaches, technologies, and scientific domains needed to achieve the goals of this proposal. We have elected to focus on understanding the fundamental inner workings of Ewing sarcoma from its transcriptional circuits, to the direct protein interactions with EWS-FLI1, to the direct and immediate effects of EWS-FLI1 degradation. Moreover, a strong emphasis of this proposal is on target identification and preclinical validation, critical steps in the process of bringing forward therapies with optimal chances for success in the clinic. The team that is assembled has all of the component pieces needed for success. Our Center includes outstanding basic cancer biologists, chemists, computational biologists, and translational researchers, and five pediatric oncologists. Thus, the proposed Center can catalyze basic discovery and clinical translation by leveraging basic and clinical research talent within the Center and our strong ties to outside academic and industrial partners.