Therapeutic degradation of Capicua (CIC) fused oncoproteins in undifferentiated sarcomas

未分化肉瘤中 Capicua (CIC) 融合癌蛋白的治疗性降解

• 批准号: 10299485
• 负责人: Ross Okimoto
• 金额: $ 36.94万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-17 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10299485
• 关键词: Adolescent and Young Adult; Affect; Binding; Binding Sites; Biochemical; Biological; Biology; CCNE1 gene; Cell Survival; Cells; Cessation of life; ChIP-seq; Child; Chromosomal translocation; Clinical; Cytogenetics; DNA; DUSP6 protein; Data; Development; Dissection; EGF gene; ETV4 gene; EWSR1 gene; Family member; Fusion Oncogene Proteins; Gene Expression Regulation; Genetic; Genetic Transcription; Genetic study; Goals; Homeobox; Human; Hyperactivity; Intercept; Laboratories; Ligands; MAPK3 gene; Malignant Neoplasms; Maps; Mediating; Methods; Mitogen-Activated Protein Kinases; Molecular; Molecular Abnormality; Mutagenesis; Neoplasm Metastasis; Nuclear; Oncogenic; Oncoproteins; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacology; Pharmacology Study; Property; Proteins; Public Health; Regulation; Research; Role; Signal Pathway; Signal Transduction; Soft Tissue Neoplasms; Structure; Target Populations; Testing; Therapeutic; Ubiquitination; Undifferentiated; base; design; effective therapy; experimental study; improved; improved outcome; innovation; insight; live cell imaging; malignant phenotype; multicatalytic endopeptidase complex; neoplastic cell; pre-clinical; programs; protein degradation; protein expression; sarcoma; survival outcome; therapeutically effective; transcription factor; tumor; tumor growth

PROJECT SUMMARY/ABSTRACT The CIC-DUX4 fusion oncoprotein is the molecular hallmark of a highly lethal subset of undifferentiated sarcomas that affects children, adolescents, and young adults (AYA). We have recently revealed critical transcriptional programs downstream of CIC-DUX4 that drive malignant phenotypes, including tumor growth and metastasis. Additionally, recent studies demonstrate that Capicua (CIC) protein expression is directly modulated by the mitogen-activated protein kinase (MAPK)-signaling pathway. The long-term goal of our laboratory is to identify and dissect the critical molecular pathways that regulate fusion oncoprotein stability and expression in human sarcoma. Our studies will reveal fusion oncoprotein-specific vulnerabilities that can facilitate precision-based therapeutic design to improve outcomes for patients with universally lethal forms of sarcomas. The objective of this proposal is to fuse our expertise in Capicua (CIC) biology and MAPK signaling to develop the first precision-based therapeutic approach for CIC-DUX4 sarcomas. We hypothesize, that genetic or pharmacologic MAPK activation will lead to the degradation of the CIC-DUX4 oncoprotein. Our rationale is based on our prior studies demonstrating MAPK-mediated regulation of wild-type (non-fused) CIC protein expression in the context of human cancer. Our specific aims will test the following hypotheses: (Aim 1) human ERK physically interacts with nuclear CIC-DUX4; (Aim 2) MAPK-ERK pathway activation decreases CIC-fused oncoprotein stability, leading to degradation; and (Aim 3) pharmacologic activation of the MAPK pathway decreases tumor cell survival through rapid degradation of the CIC-DUX4 fusion oncoprotein. The significance of these findings are highly impactful, as there are no effective therapeutic strategies to target CIC- DUX4 sarcomas, which remain lethal in the metastatic setting. Our proposal is innovative because we are leveraging our expertise in MAPK-signaling, transcription factor fusions, and Capicua biology to develop a precision-based therapeutic approach to directly target and degrade a lethal fusion oncoprotein in sarcoma, an unmet scientific and clinical need.

项目摘要/摘要 CIC-DUX4融合癌蛋白是一个高度致命的未分化子集的分子标志 影响儿童，青少年和年轻人的肉瘤（AYA）。我们最近揭示了关键 CIC-DUX4下游的转录程序驱动恶性表型，包括肿瘤生长 和转移。此外，最近的研究表明，Capicua（CIC）蛋白表达直接 由有丝分裂原激活的蛋白激酶（MAPK）信号途径调节。我们的长期目标 实验室将识别和剖析调节融合癌蛋白稳定性和的关键分子途径 在人类肉瘤中的表达。我们的研究将揭示融合癌蛋白特异性脆弱性 促进基于精确的治疗设计，以改善具有普遍致命形式的患者的预后 肉瘤。该建议的目的是融合我们在Capicua（CIC）生物学和MAPK信号传导方面的专业知识 为CIC-DUX4肉瘤开发了第一种基于精确的治疗方法。我们假设，那是 遗传或药理学MAPK激活将导致CIC-DUX4癌蛋白的降解。我们的 基本原理是基于我们先前的研究，证明了MAPK介导的野生型（未融合）CIC的调节 蛋白质在人类癌症的背景下。我们的具体目的将检验以下假设：（目标1） 人类ERK与核CIC-DUX4物理相互作用； （AIM 2）MAPK-ERK途径激活减少 CIC融合的癌蛋白稳定性，导致降解； （AIM 3）MAPK的药理激活 途径通过CIC-DUX4融合量蛋白的快速降解来降低肿瘤细胞的存活。这 这些发现的重要性具有很高的影响力，因为没有有效的治疗策略来针对CIC- Dux4肉瘤，在转移环境中仍然致命。我们的建议是创新的，因为我们是 利用我们在MAPK信号，转录因子融合和Capicua生物学方面的专业知识来发展 基于精确的治疗方法直接靶向和降解肉瘤中致命融合癌蛋白 未满足的科学和临床需求。