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（Glioblastoma， GBM）是一种由小细胞瘤驱动的致死性脑癌