Role of FACT in ZFTA-RelA fusion driven ependymoma

FACT 在 ZFTA-RelA 融合驱动的室管膜瘤中的作用

基本信息

批准号：
10638244
负责人：
Stephen C Mack
金额：
$ 72.09万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10638244
关键词：
Accounting Adult Antineoplastic Agents Biological Process Brain Brain Neoplasms CRISPR/Cas technology Cancer Etiology Cell Culture Techniques Cell Survival Cell model Cells Childhood Brain Neoplasm Chimeric Proteins Chromatin Chromatin Remodeling Factor Classification Clinical Trials Clinical Trials Design Combined Modality Therapy Data Dependence Development Disease Dominant-Negative Mutation Dose Ependymoma Event Future Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription Genetic study Goals Growth Hippocampus Human Immune Infiltration Inflammation Inflammatory Knock-out Lead Maintenance Malignant Neoplasms Malignant neoplasm of brain Mediating Methods Modeling Molecular Mus Myeloid Cells Neuroglia Nucleosomes Oncogenes Oncogenic Pathway interactions Patient-Focused Outcomes Patients Pediatric Brain Tumor Consortium Pediatric Neoplasm Phenotype Prognosis Proteins RELA gene RNA Polymerase II Radial Radiation therapy Role Signal Transduction Solid Neoplasm Spinal Cord Subgroup Supratentorial Testing Therapeutic Transcription Elongation Translating Tumorigenicity Undifferentiated United States National Institutes of Health antitumor effect blood-brain barrier penetration brain tissue chemotherapy childhood cancer mortality chromatin remodeling clinically relevant disorder subtype effective therapy immune cell infiltrate immunoregulation improved in vivo insight loss of function mouse model neoplastic neoplastic cell nerve stem cell neurogenesis new therapeutic target novel therapeutics pharmacologic phase I trial pre-clinical prevent programs recruit self-renewal small molecule standard of care stem stem cell self renewal stem cells survival outcome targeted treatment therapeutic target transcriptome tumor tumor growth tumor microenvironment tumor progression

项目摘要

PROJECT SUMMARY / ABSTRACT Ependymomas are tumors that occur in the brain or spinal cord and are incurable in nearly half of all patients. Recent molecular classification has identified numerous molecular subgroups of ependymoma with supratentorial ependymoma ZFTA-RELA fusion positive (ZFTA-RELA) accounting for over 70% of all supratentorial ependymomas. ZFTA-RELA, a mainly pediatric brain tumor, has also been identified as one of the subgroups with the worst prognosis. These tumors arise from the oncogenic fusion between a central gene in the NF-κB pathway, RELA, and a gene with undescribed function, ZFTA. The resulting fusion protein, ZRfus, aberrantly recruits transcriptional and chromatin remodeling machinery to drive neoplastic transcriptional programs that includes constitutive activation of NF-κB signaling, activation of inflammatory gene expression programs, and stem cell programs. To date, chemotherapy has not become standard of care for any of the subtypes of ependymoma. All targeted therapies tested in ependymoma clinical trials have failed. Therefore, there is an urgent need to capitalize on the more recent molecular understanding of ZFTA-RELA to develop novel therapeutic paradigms that increase survival outcomes for these patients. In the search for co-regulatory proteins as candidate tumor dependencies and targets, we identified the chromatin remodeling complex, FACT (FAcilitates Chromatin Transcription), as a ZRfus interacting protein. Moreover, FACT is elevated in ZFTA-RELA compared to normal brain tissue and other ependymoma disease subtypes. Project goal: To thoroughly investigate FACT as a driver of ZFTA-RELA and to reveal it as a promising therapeutic target for this devastating disease. FACT, a heterodimer of SPT16 and SSRP1, mainly serves to reorganize nucleosomes to facilitate RNA polymerase II-mediated transcription. In tumors, we and others have shown that FACT is essential for maintaining an undifferentiated stem-like state necessary for tumor growth. This is relevant for ZFTA-RELA tumors as they are characterized as having undifferentiated transcriptional profiles. Project hypothesis: FACT regulates ZRfus oncogenic and inflammatory genes to maintain an undifferentiated cell state. Compromising FACT function will lead to reduced tumor growth, modulate tumor inflammation, and improve survival in orthotopic murine tumor models. Aim 1: Determine if FACT is essential for sustaining transcription of ZRfus targets (including oncogenes and inflammatory genes) and stem cell identity genes that may be important for tumorigenicity. Impact: These studies will reveal how FACT regulates ZRfus transcription and tumor cell identity. Aim 2: Evaluate the impact of genetic and pharmacological disruption of FACT on tumor progression, immune landscape, overall survival, and normal neurogenesis. Impact: These studies will reveal preclinical insight into FACT as a therapeutic target, and the efficacy of our candidate small molecule anti-neoplastic as rationale therapy to inform future clinical trial design. Overall, successful completion of our studies will reveal new therapeutic options for ZFTA-RELA ependymoma that can rapidly be moved into clinical trials.

项目概要/摘要室管膜瘤是发生在大脑或脊髓的肿瘤，近一半的患者无法治愈。最近的分子分类已经确定了室管膜瘤的许多分子亚组幕上室管膜瘤ZFTA-RELA融合阳性（ZFTA-RELA）占总数的70%以上幕上室管膜瘤，一种主要是儿童脑肿瘤，也被确定为其中之一。这些肿瘤是由中心基因之间的致癌融合引起的。 NF-κB 通路 RELA 和具有未描述功能的基因 ZFTA 由此产生的融合蛋白 ZRfus，异常地招募转录和染色质重塑机制来驱动肿瘤转录程序包括 NF-κB 信号传导的组成型激活、炎症基因表达的激活迄今为止，化疗尚未成为任何治疗的标准。室管膜瘤的所有亚型临床试验都失败了。迫切需要利用 ZFTA-RELA 的最新分子理解来开发寻求共同监管以提高这些患者的生存结果。蛋白质作为候选肿瘤依赖性和靶标，我们鉴定了染色质重塑复合物，FACT （促进染色质转录），作为 ZRfus 相互作用蛋白，此外，FACT 在 ZFTA-RELA 中升高。与正常脑组织和其他室管膜瘤疾病亚型相比项目目标：彻底。研究 FACT 作为 ZFTA-RELA 的驱动因素，并揭示其作为这种毁灭性的一种有希望的治疗靶点 FACT是SPT16和SSRP1的异二聚体，主要用于重组核小体以促进RNA。我们和其他人已经证明，FACT 对于肿瘤中聚合酶 II 介导的转录至关重要。维持肿瘤生长所需的未分化干细胞状态，这与 ZFTA-RELA 相关。肿瘤，因为它们的特征是具有未分化的转录谱。项目假设：FACT。调节 ZRfus 致癌和炎症基因以维持未分化的细胞状态。 FACT 功能将导致减少肿瘤生长、调节肿瘤炎症并提高生存率原位小鼠肿瘤模型目标 1：确定 FACT 是否对于 ZRfus 的维持转录至关重要。靶标（包括癌基因和炎症基因）和干细胞识别基因可能对影响：这些研究将揭示 FACT 如何调节 ZRfus 转录和肿瘤细胞身份。目标 2：评估 FACT 的遗传和药理学破坏对肿瘤进展、免疫的影响影响：这些研究将揭示临床前的见解。 FACT 作为治疗靶点，以我们候选小分子抗肿瘤药物的功效作为基本原理总体而言，我们研究的成功完成将揭示新的内容。 ZFTA-RELA 室管膜瘤的治疗方案可以迅速进入临床试验。