Therapeutic Targeting of WDR5 in the Glioblastoma Perivascular Niche

WDR5 在胶质母细胞瘤血管周围微环境中的治疗靶向

• 批准号: 10581400
• 负责人: Christopher G Hubert
• 金额: $ 45.66万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581400
• 关键词: 3-Dimensional; Biology; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Neoplasms; CRISPR/Cas technology; Cell Fraction; Cell Maintenance; Cell Proliferation; Cells; Chromatin; Clinical; Combined Modality Therapy; Complex; Data; Disease; Dose; Epigenetic Process; Essential Genes; Evaluation; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Glioblastoma; Goals; Growth; Histones; Hypoxia; Immunohistochemistry; Individual; Intracranial Neoplasms; Label; Lysine; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Methodology; Methods; Methylation; Modeling; Necrosis; Normal Cell; Nutrient; Organoids; Outcome; Patients; Pharmaceutical Preparations; Population; Pre-Clinical Model; Primary Brain Neoplasms; Property; Proteins; Proto-Oncogenes; Radiation therapy; Recurrence; Research; Resistance; Resolution; Role; Signal Transduction; Slice; Solid Neoplasm; Structure; System; Techniques; Testing; Therapeutic; Thick; Treatment Efficacy; Tumor Biology; WD Repeat; Work; blood-brain barrier penetration; cancer type; candidate validation; chromatin immunoprecipitation; confocal imaging; embryonic stem cell; improved; in vivo; inhibitor; innovation; mouse model; novel; novel strategies; novel therapeutic intervention; patient derived xenograft model; pharmacologic; pre-clinical; prevent; programs; promoter; rational design; reconstruction; screening; self-renewal; senescence; standard of care; stem; stem cell biomarkers; stem cell growth; stem cell proliferation; stem cell self renewal; stem cells; stem-like cell; temozolomide; therapeutic target; therapy resistant; transcriptome sequencing; tumor; tumor hypoxia; tumor microenvironment; tumorigenic

PROJECT SUMMARY / ABSTRACT: Glioblastoma (GBM) is a uniformly fatal brain cancer driven by a small population of self-renewing, highly tumorigenic cells termed GBM stem cells (GSCs). Our long-term goal is to find improved therapeutics for GBM by better understanding the biology that drives this disease. GBM tumors have a complex microenvironment including a relatively proliferative perivascular niche containing GSCs enriched for the stem cell marker SOX2+, and a distinct hypoxic niche that regulates resident GSCs through hypoxic signaling factors. Because the cells within distinct GBM tumor regions are remarkably different from each other, we believe that individual tumor microenvironments must be targeted with unique niche-specific therapies. However, current culture models fail to replicate the complex microenvironments of GSCs, limiting our ability to study and therapeutically target GBM. We therefore developed patient-derived GBM organoids, a controlled ex-vivo system that contains both proliferative and hypoxic niches, as well as gradients of stem and non-stem cells similar to those observed in patient tumors. We developed methods to 3-dimensionally label the separate niches of organoid cultures and used these techniques to perform the first spatially-resolved functional screen in any solid tumor. Our results pinpointed the epigenetic effector protein WDR5 as being uniquely essential to GSCs growing in the proliferative niche of GBM organoids. The objective of this application is to illuminate the roles of WDR5 in glioblastoma and determine whether disruption of WDR5 activity may have therapeutic efficacy. To achieve this, we will test the central hypothesis that GSCs require WDR5 to maintain bivalent gene expression within proliferative tumor niches, and that WDR5 can be targeted to compromise GBM growth in vivo. We will test this through execution of the following specific Aims: 1) determine if WDR5 activity is required for niche-specific GSC growth in vivo, 2) determine if WDR5 creates embryonic stem-cell-like bivalent gene regulation in GBM, and 3) determine if targeting of WDR5 function yields a therapeutic benefit in GBM preclinical models. The proposed research is an innovative first-of-its-kind study that will verify the feasibility and efficacy of niche-specific targeted screening and drug identification. This represents a significant advancement by using novel methodology and feasible new approaches to overcome an experimental barrier across many cancer types. This conceptual and experimental framework can be applied to a wide range of cancers, can unmask unique microenvironmental biology, and can allow rationally designed combination therapies against niche-specific targets. The expected outcome of this work is an understanding of the roles of WDR5 in GBM niche biology and evaluation of a novel blood-brain-barrier penetrant WDR5 inhibitor in orthotopic brain tumors. There is an urgent need to develop novel therapeutic strategies that significantly improve the survival of GBM patients. This proposal will investigate the mechanistic role of WDR5 in GBM biology, while simultaneously testing a promising potential therapeutic in highly accurate preclinical models.

项目摘要/摘要：胶质母细胞瘤 (GBM) 是一种由小细胞驱动的致命性脑癌。 自我更新、高致瘤性细胞群，称为 GBM 干细胞 (GSC)。我们的长期目标是 通过更好地了解驱动 GBM 的生物学原理，找到改进的 GBM 治疗方法。 GBM肿瘤 具有复杂的微环境，包括含有 GSC 的相对增殖的血管周围生态位 富含干细胞标记物 SOX2+，以及通过调节常驻 GSC 的独特缺氧生态位 缺氧信号因子。因为不同 GBM 肿瘤区域内的细胞与 彼此之间，我们相信个体肿瘤微环境必须针对独特的利基特异性 疗法。然而，当前的培养模型无法复制 GSC 的复杂微环境，限制了我们的研究 研究和治疗靶向 GBM 的能力。因此，我们开发了源自​​患者的 GBM 类器官， 受控的离体系统，包含增殖和缺氧生态位，以及干和梯度 与在患者肿瘤中观察到的非干细胞相似。我们开发了 3 维标记方法 分离类器官培养物的利基，并使用这些技术执行第一个空间分辨功能 筛查任何实体瘤。我们的结果表明表观遗传效应蛋白 WDR5 是独一无二的 对于在 GBM 类器官的增殖生态位中生长的 GSC 至关重要。该应用程序的目的是 阐明 WDR5 在胶质母细胞瘤中的作用并确定 WDR5 活性的破坏是否可能对 治疗功效。为了实现这一目标，我们将测试 GSC 需要 WDR5 来维持的中心假设 增殖性肿瘤微环境中的二价基因表达，并且 WDR5 可以靶向 损害 GBM 在体内的生长。我们将通过执行以下具体目标来测试这一点：1) 确定 WDR5 活性是否是体内特定生态位 GSC 生长所必需的，2) 确定 WDR5 是否产生 GBM 中的胚胎干细胞样二价基因调控，以及 3) 确定 WDR5 功能的靶向是否产生 GBM 临床前模型中的治疗益处。拟议的研究是一项创新性的首创研究 这将验证针对特定利基的靶向筛选和药物鉴定的可行性和有效性。这 代表了通过使用新颖的方法和可行的新方法来克服的重大进步 跨多种癌症类型的实验屏障。这个概念和实验框架可以应用 对于多种癌症，可以揭示独特的微环境生物学，并且可以允许合理设计 针对利基特定目标的联合疗法。这项工作的预期成果是了解 WDR5 在 GBM 生态位生物学中的作用以及新型血脑屏障渗透性 WDR5 抑制剂的评估 在原位脑肿瘤中。迫切需要开发新的治疗策略，以显着 提高 GBM 患者的生存率。该提案将研究 WDR5 在 GBM 中的机制作用 生物学，同时在高度准确的临床前模型中测试一种有前途的潜在治疗方法。