The Center for Therapeutic Targeting of EWS-oncoproteins

EWS癌蛋白治疗靶向中心

• 批准号: 10382013
• 负责人: SCOTT A ARMSTRONG
• 金额: $ 19.83万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10382013
• 关键词: Award; Basic Science; Biology; Chemicals; Chimeric Proteins; Clinic; Clinical Research; Complex; Computational Biology; Development; Disease; EWS-FLI1 fusion protein; Epigenetic Process; Ewings sarcoma; Functional disorder; Genetic Transcription; Goals; Individual; Industrialization; Institution; Investigational Therapies; Knowledge; Malignant Neoplasms; Molecular; Oncogenic; Oncoproteins; Parents; Pediatric Oncologist; Process; Proteins; Research; Talents; Technology; Therapeutic; Therapeutic Clinical Trial; Translations; Validation; bone; clinical translation; drug development; improved outcome; mouse model; novel; novel therapeutics; pediatric patients; pre-clinical; sarcoma; skills; structural biology; success; therapeutic target; tool; translational scientist; tumorigenesis

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.

项目总结：总体 本节与U 54 CA 231637母公司奖相同。 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，并研究新的治疗方法和治疗机制，以改善 对于患有这种侵袭性疾病的儿科患者的结果。分子翻译 了解肉瘤的病理生理学转化为有效的新药在临床上是一个复杂的， 这需要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、小鼠 模型、临床前实验治疗和临床试验开发。中心机制是 这对该提案的成功至关重要。没有任何一个机构或个人可以掌握的多样性， 实现本提案目标所需的方法、技术和科学领域。我们有 当选为重点了解尤文肉瘤的基本内部运作，从其 转录电路，与EWS-FLI 1的直接蛋白质相互作用，直接和立即 EWS-FLI 1降解的影响。此外，这项建议的重点是目标 鉴定和临床前验证，提出最佳治疗方法的过程中的关键步骤 在临床上取得成功的机会。组建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， 和翻译研究人员，以及五名儿科肿瘤学家。因此，拟议的中心可以催化碱性 通过利用中心内的基础和临床研究人才， 与外部学术和工业合作伙伴的紧密联系。