The Center for Therapeutic Targeting of EWS-oncoproteins

项目总结：总体 本节与U 54 CA 231637母公司合同相同 该中心的主要科学重点是了解EWS-ETS驱动的分子基础 尤文肉瘤，并研究新的治疗方法和治疗机制，以改善预后， 患有这种侵袭性疾病的儿科患者。肉瘤的分子理解翻译 将病理生理学转化为临床上有效的新药是一个复杂的、有风险的命题， 一个由具有互补技能的人才组成的团队的协调努力。该小组将专业知识 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，小鼠模型，临床前实验 治疗和临床试验开发。一个中心的机制对这项建议的成功至关重要。 没有一个机构或个人能够掌握方法、技术和科学的多样性， 实现本提案目标所需的领域。我们选择把重点放在理解 尤文肉瘤的基本内部运作，从转录电路到直接的蛋白质相互作用， 与EWS-FLI 1，EWS-FLI 1降解的直接和立即的影响。此外，强烈强调 该提案的重点是目标识别和临床前验证，这是将 在临床上具有最佳成功机会的前瞻性疗法。集合起来的团队拥有所有 成功所需的组成部分。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、翻译研究人员和五名儿科肿瘤学家。因此，拟议的 中心可以通过利用基础和临床研究人才来促进基础发现和临床转化 中心内部以及我们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.