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

• 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
• 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

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.

项目总结/摘要 室管膜瘤是发生在脑或脊髓中的肿瘤，并且在所有患者中几乎一半是不可治愈的。 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70%以上 幕上室管膜瘤。ZFTA-RELA是一种主要的儿科脑肿瘤，也被确定为 预后最差的亚组。这些肿瘤是由一个中心基因 在NF-κB通路中，RELA和一个功能未知的基因ZFTA。得到的融合蛋白ZRfus， 异常地募集转录和染色质重塑机制以驱动肿瘤性转录 包括NF-κB信号传导的组成性激活、炎症基因表达的激活 项目和干细胞项目。到目前为止，化疗尚未成为任何癌症患者的标准治疗。 室管膜瘤的亚型室管膜瘤临床试验中测试的所有靶向治疗都失败了。因此，我们认为， 迫切需要利用最近对ZFTA-RELA的分子理解来开发 新的治疗模式，增加这些患者的生存结果。在寻求共同监管 作为候选肿瘤依赖性和靶点，我们鉴定了染色质重塑复合物，FACT （FACilitates Chromatin Transcription），作为ZRfus相互作用蛋白。此外，在ZFTA-RELA中FACT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，并揭示它作为这种破坏性疾病的有希望的治疗靶点， 疾病FACT是SPT 16和SSRP 1的异源二聚体，主要用于重组核小体以促进RNA 聚合酶II介导的转录。在肿瘤中，我们和其他人已经表明，FACT是必不可少的， 维持肿瘤生长所必需的未分化的干细胞样状态。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：事实 调节ZRfus致癌和炎症基因以维持未分化的细胞状态。损害 FACT功能将导致肿瘤生长减少，调节肿瘤炎症，并改善患者的生存率。 原位鼠肿瘤模型。目的1：确定FACT是否是维持ZRfus转录所必需的 靶基因（包括致癌基因和炎症基因）和干细胞身份基因，这些基因可能对 致瘤性影响：这些研究将揭示FACT如何调节ZRfus转录和肿瘤细胞身份。 目的2：评价FACT的遗传和药理学破坏对肿瘤进展、免疫功能和预后的影响。 景观、总体生存率和正常神经发生。影响：这些研究将揭示临床前洞察， FACT作为治疗靶点，我们的候选小分子抗肿瘤药物的疗效作为依据 为未来的临床试验设计提供信息。总的来说，成功完成我们的研究将揭示新的 ZFTA-RELA室管膜瘤的治疗选择，可以迅速进入临床试验。