Selective targeting of ependymoma progenitor cells via BMI1 inhibition

通过 BMI1 抑制选择性靶向室管膜瘤祖细胞

基本信息

批准号：
10648408
负责人：
Rajeev Vibhakar
金额：
$ 21.81万
依托单位：
UNIVERSITY OF COLORADO DENVER
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：
2023-04-20 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10648408
关键词：
Address BMI1 gene Brain Cell Line Cells Chemicals Child Childhood Childhood Brain Neoplasm Chromatin Clinical Trials Data Dependence Development Ependymoma Epigenetic Process Follow-Up Studies Funding Future Genetic Genomics Growth Heterogeneity Human In Vitro Mediating Modification Molecular Analysis Molecular Biology Normal Cell Operative Surgical Procedures Outcome PRC1 Protein Patients Pediatric Neoplasm Pediatrics Phenotype Population Posterior Fossa Prognosis Prognostic Marker Proteins RNA interference screen Radiation Radiation therapy Refractory Regulation Role Sampling Subgroup Supratentorial Testing Therapeutic Treatment Efficacy Tumor Stem Cells Undifferentiated Validation Work Xenograft procedure cancer cell cell behavior cell growth chemotherapy clinical development clinically relevant efficacy testing epigenome high risk high risk population immune cell infiltrate improved improved outcome in vivo in vivo Model inhibitor innovation neoplastic cell novel novel therapeutic intervention patient derived xenograft model pre-clinical progenitor self-renewal single-cell RNA sequencing small molecule inhibitor stem stem cell differentiation stem cells trial design tumor tumorigenesis tumorigenic

项目摘要

PROJECT SUMMARY Ependymoma (EPN) is fatal in 50% of children and has not seen any therapeutic improvements in over 30 years. Standard therapy remains limited to surgery, radiation, and chemotherapy in limited situations. In the past decade our understanding of the molecular biology of EPN has been advanced by molecular analysis of patient samples but these advances have failed to improve outcomes. Genomic studies clearly define multiple subgroups including Posterior fossa A and B as well as supratentorial subgroups. Despite these advances the heterogeneity in EPN remains a problem. To address this problem, we performed single cell RNA sequencing analysis of EPN patient samples and identified an undifferentiated progenitor population that expresses high levels of pluripotent cell markers. In parallel we performed an unbiased epigenome-wide RNAi screen targeting 410 chromatin regulators to identify novel epigenetic regulators critical for EPN cell growth. We identified the Polycomb repressive complex 1 (PRC1) protein BMI1 as a top hit, that when depleted or chemically inhibited severely suppressed EPN cell growth. Interestingly BMI1 is most highly expressed in the undifferentiated population identified by our scRNA-seq and associated with worse outcomes. Importantly the functional significance of BMI1 has not previously been evaluated in EPN. We hypothesize that high expression of BMI1 promotes de-differentiation and self-renewal of the UEC subpopulation, thereby locking the cells in a highly tumorigenic stem-like state. To address our hypothesis, we will first investigate the inhibition of BMI1 function on PFA tumor cell self-renewal and differentiation of aggressive PFA subpopulations in vitro. We will then establish the therapeutic efficacy of targeting BMI1 with novel small molecule inhibitors in EPN in vivo. Completion of this work will establish a direct role for BMI1 in EPN stem cell differentiation and provide justification for use of BMI1 inhibitors in human pediatric clinical trials.

项目摘要 50％的儿童中膜瘤（EPN）是致命的，尚未看到任何治疗性超过30年的改进。标准疗法仍然仅限于手术，辐射，和在有限情况下化学疗法。在过去的十年中，我们对 EPN的分子生物学已通过对患者样品的分子分析进行了提高但是这些进步未能改善结果。基因组研究明确定义了多个子组，包括后窝A和B以及上关。尽管如此，EPN的异质性仍然是一个问题。解决这个问题问题，我们对EPN患者样品进行了单细胞RNA测序分析和确定了一个未分化的祖先人群，表达高水平多能细胞标记。在平行的情况下，我们进行了无偏的表观基因组RNAi 筛选靶向410个染色质调节剂以识别新型表观遗传调节剂关键用于EPN细胞生长。我们确定了Polycomb抑制复合物1（PRC1）蛋白 BMI1是最高的命中，当耗尽或化学抑制时严重抑制EPN时细胞生长。有趣的是，BMI1在未分化的人群中最高表达由我们的scrna-seq确定，并与较差的结果相关。重要的是 BMI1的功能意义先前尚未在EPN中进行评估。我们假设BMI1的高表达促进了脱节和自我更新 UEC亚群，从而将细胞锁定在高度肿瘤的茎状状态下。为了解决我们的假设，我们将首先研究BMI1功能对PFA的抑制肿瘤细胞自我更新和体外PFA亚群的分化。我们然后，将建立用新型小分子靶向BMI1的治疗功效 EPN体内抑制剂。这项工作的完成将为BMI1建立直接角色 EPN干细胞分化并为人类使用BMI1抑制剂提供了理由小儿临床试验。