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

项目总结/摘要 CIC-DUX 4融合癌蛋白是高度致死的未分化癌细胞亚群的分子标志。 肉瘤影响儿童，青少年和年轻人（AYA）。我们最近发现 CIC-DUX 4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）蛋白的表达是直接的， 由丝裂原活化蛋白激酶（MAPK）信号通路调节。我们的长期目标是 该实验室的目的是鉴定和剖析调节融合癌蛋白稳定性的关键分子途径， 在人肉瘤中的表达。我们的研究将揭示融合癌蛋白特异性的脆弱性， 促进基于精确度的治疗设计，以改善具有普遍致命形式的患者的结局。 肉瘤本提案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-DUX 4肉瘤开发第一种基于精确度的治疗方法。我们假设， 遗传或药理学MAPK激活将导致CIC-DUX 4癌蛋白的降解。我们 基本原理是基于我们先前的研究，证明MAPK介导的野生型（非融合）CIC的调节 蛋白质在人类癌症中的表达。我们的具体目标将测试以下假设：（目标1） 人ERK与核CIC-DUX 4物理相互作用;（目的2）MAPK-ERK通路活化降低 CIC融合的癌蛋白稳定性，导致降解;和（目的3）MAPK的药理学激活 CIC-DUX 4通路通过CIC-DUX 4融合癌蛋白的快速降解降低肿瘤细胞存活。的 这些发现的意义是非常有影响力的，因为没有有效的治疗策略来靶向CIC- DUX 4肉瘤，在转移性环境中仍然致命。我们的建议是创新的，因为我们是 利用我们在MAPK信号传导，转录因子融合和Capicua生物学方面的专业知识， 一种基于精确度的治疗方法，直接靶向并降解肉瘤中的致命融合癌蛋白， 未满足的科学和临床需求。

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.