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.

项目摘要 /摘要 室系膜瘤是在大脑或脊髓中发生的肿瘤，几乎一半的患者都无法治愈。 最近的分子分类已经确定了许多分子亚组的沉积物瘤 sefentorial recondymoma ZFTA-RELA融合阳性（ZFTA-RELA）占所有超过70％ 刚毛膜瘤。 Zfta-Rela是一种主要是儿科脑肿瘤，也被确定为 预后最差的亚组。这些肿瘤来自中央基因之间的致癌融合 在NF-κB途径中，RELA和具有未描述功能的基因ZFTA。由此产生的融合蛋白Zrfus， 异常募集转录和染色质重塑机械以驱动肿瘤转录 包括NF-κB信号传导的本构激活的程序，炎症基因表达的激活 程序和干细胞程序。迄今为止，化学疗法尚未成为任何一项的护理标准 室管膜瘤的亚型。在室温瘤临床试验中测试的所有靶向疗法均失败。所以， 迫切需要利用最近对ZFTA-Rela的分子理解来发展 这些患者增加生存结果的新型热范式。在寻求共同调节 蛋白质作为候选肿瘤依赖性和靶标，我们确定了染色质重塑复合物，事实 （促进染色质转录），作为Zrfus相互作用的蛋白质。而且，ZFTA-RELA中的事实提升了 与正常的脑组织和其他疾病亚型相比。项目目标：彻底 研究事实是ZFTA-RELA的驱动程序，并将其视为这一毁灭性的有前途的治疗目标 疾病。事实，SPT16和SSRP1的异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，我们和其他人表明，事实对于 维持对肿瘤生长所必需的未分化的类似茎状状态。这与Zfta-Rela有关 肿瘤的特征是没有分化的转录曲线。项目假设：事实 调节Zrfus致癌基因和炎症基因维持未分化的细胞态。妥协 事实功能将导致肿瘤生长减少，调节肿瘤注射并改善 原位鼠肿瘤模型。目标1：确定事实对于维持Zrfus的转录至关重要 靶标（包括癌基因和炎症基因）和干细胞同一性基因可能对 肿瘤性。影响：这些研究将揭示事实如何调节ZRFUS转录和肿瘤细胞身份。 目标2：评估事实的遗传和药物破坏对肿瘤进展，免疫的影响 景观，整体生存和正常神经发生。影响：这些研究将揭示临床前的见解 作为治疗靶标的事实，以及我们候选人小分子抗塑性的效率作为理由 用于告知未来临床试验设计的治疗。总体而言，我们的研究成功完成将揭示新的 可以快速移动到临床试验中的ZFTA-RELA膜状膜瘤的治疗选择。