Epigenetically regulated stemness program and stem cell niche as targets in pediatric DIPG

表观遗传调控的干细胞程序和干细胞生态位作为儿科 DIPG 的目标

• 批准号: 10635435
• 负责人: Stefanie Galban
• 金额: $ 43.79万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10635435
• 关键词: Acceleration; Address; Aldehydes; Automobile Driving; Biological Assay; CASP3 gene; Cancer Biology; Cell Differentiation process; Cells; Characteristics; Chemotherapy and/or radiation; Childhood; Childhood Brain Neoplasm; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Coculture Techniques; Combined Modality Therapy; DNA Repair Gene; Data; Development; Diagnosis; Diffuse intrinsic pontine glioma; Disease; Disulfiram; Dose; Drug Synergism; Drug resistance; Epigenetic Process; Exhibits; FRAP1 gene; Gliomagenesis; Goals; H3 K27M mutation; Histones; Hydrogenase; Immune; Immune Evasion; Immunity; Immunosuppression; In Vitro; Interleukin-1 beta; Intervention Studies; Knowledge; Literature; Malignant Childhood Neoplasm; Metabolism; Methylation; Microglia; Modeling; Mutation; Natural History; Outcome; PIK3CG gene; Patients; Penetrance; Pharmaceutical Preparations; Phase I Clinical Trials; Protein Isoforms; Public Health; Publications; Radiation Tolerance; Radiation therapy; Recurrence; Recurrent tumor; Regulation; Relapse; Reporter; Reporting; Research; Resistance; Resistance development; Role; Scheme; Signal Pathway; Signal Transduction; Small Interfering RNA; Technology; Therapeutic; Therapeutic Intervention; Treatment Efficacy; Tumor Immunity; Tumor Promotion; aldehyde dehydrogenases; cancer cell; cancer stem cell; clinical predictors; clinical translation; combinatorial; design; druggable target; efficacious treatment; in vivo; inhibitor; innovation; mTOR Inhibitor; mTOR inhibition; mortality; mouse model; multidisciplinary; mutant; novel therapeutics; oncohistone; overexpression; pre-clinical; preclinical study; prevent; programs; radiation resistance; radioresistant; resistance mechanism; response; single-cell RNA sequencing; standard of care; stem; stem cell biology; stem cell niche; stem cells; stemness; synergism; targeted treatment; therapeutic development; therapy resistant; transcriptomics; translational therapeutics; tumor; tumor initiation; tumor microenvironment; tumor progression

Understanding the role of cancer stem cells (CSCs) in diffuse intrinsic pontine glioma (DIPG) is crucial for preventing treatment resistance and tumor progression and for devising therapies that may prolong the lives of the 200-400 pediatric DIPG patients diagnosed each year. Radiotherapy remains the standard of care, but tumors recur in 100% of patients, resulting in dismal patient survival of 8-11 months. Over 250 clinical trials have failed to move these numbers. Mechanistic research is urgently needed to understand the underlying biology of CSCs and how they drive treatment resistance to develop innovative combinatorial therapies that can change the natural history of DIPG. Extensive preliminary data and existing literature, support the overarching hypothesis that aldehyde hydrogenase positive (ALDH+) CSC cause therapeutic resistance and drive tumor progression. We propose, in mechanistic studies, to characterize an epigenetically regulated stemness program and stem cell niche (Aim 1 and 2) as potential targets (Aim 3) in pediatric DIPG. Specifically, in Aim 1, we will determine the role and regulation of ALDH-positive CSCs in DIPG. We will evaluate the regulation of specific ALDH isoforms, particularly ALDH1A3 and ALDH2 by H3 K27M mutation, and by IL1β secreted by microglia, respectively, in carefully designed in vitro and in vivo assays using isogenic DIPG models. We will define the role of specific ALDH isoforms, including ALDH1A3 and ALDH2, in cell differentiation, tumor initiation and progression, and immunity. In Aim 2 we will evaluate whether ALDH+ CSCs are the cause of therapeutic resistance and responsible for tumor progression. We will modulate expression of disease relevant ALDH isoforms and evaluate whether therapeutic sensitivity can be restored. We will characterize the therapy induced stem cell niche and mechanisms of immune evasion with cutting-edge technologies, including single cell RNA sequencing (scRNA-seq) and CyTOF. In Aim 3, we will target ALDH+ CSCs as the cause of resistance to prevent tumor progression. In preclinical proof-of concept studies we will target ALDH (Disulfiram) and PI3K/mTOR (GDC- 0084), a cell intrinsic signaling of ALDH+ CSC, to enhance outcomes from standard of care (radiotherapy) and to prevent progression. Therefore, our studies will (1) confirm that CSCs present a mechanism of resistance and (2) provide a rationale to target these cells specifically and (3) address an unmet clinical need for efficacious therapies. In summary, our proposal will mechanistically address the role of ALDH+ CSCs in therapeutic resistance and tumor relapse of DIPG and provide druggable targets, which can accelerate clinical translation against this devastating pediatric disease.

了解癌症干细胞（CSC）在弥漫性内在脑桥胶质瘤（DIPG）中的作用， 对于预防治疗耐药性和肿瘤进展以及设计 可以延长每年诊断的200-400名儿童DIPG患者的生命。放疗 仍然是标准的护理，但肿瘤复发的患者100%，导致令人沮丧的患者 存活8-11个月。超过250项临床试验未能改变这些数字。机械论 迫切需要研究来了解CSC的基本生物学以及它们如何驱动 开发创新的组合疗法，可以改变自然的 DIPG的历史广泛的初步数据和现有文献，支持总体 假设醛氢化酶阳性（ALDH+）CSC引起治疗抗性， 推动肿瘤进展。我们建议，在机制的研究，表征一个表观遗传 调节干细胞程序和干细胞生态位（目标1和2）作为潜在的目标（目标3）， 小儿DIPG。具体而言，在目标1中，我们将确定ALDH阳性的作用和调节。 DIPG中的CSC。我们将评估特定ALDH亚型的调节，特别是ALDH 1A 3 H3 K27 M突变和小胶质细胞分泌的IL 1 β分别对ALDH 2和ALDH 2的表达有显著影响。 使用同基因DIPG模型设计体外和体内测定。我们将定义特定的角色 ALDH同种型，包括ALDH 1A 3和ALDH 2，在细胞分化、肿瘤发生和 进展和免疫力在目标2中，我们将评估ALDH+ CSC是否是导致 治疗抗性和负责肿瘤进展。我们将调节 与疾病相关的ALDH同种型，并评估治疗敏感性是否可以恢复。 我们将描述治疗诱导的干细胞生态位和免疫逃避机制 利用尖端技术，包括单细胞RNA测序（scRNA-seq）和CyTOF。 在目标3中，我们将靶向ALDH+ CSC作为耐药的原因，以防止肿瘤进展。 在临床前概念验证研究中，我们将靶向ALDH（双硫仑）和PI 3 K/mTOR（GDC-1）。 0084），ALDH+ CSC的细胞内在信号传导，以增强来自标准护理的结果 （放疗）和预防进展。因此，我们的研究将（1）证实CSC 提出了耐药机制和（2）提供了特异性靶向这些细胞的基本原理 和（3）解决对有效疗法的未满足的临床需求。 总之，我们的提案将机械地解决ALDH+ CSC在以下方面的作用： DIPG的治疗耐药性和肿瘤复发，并提供了可药用靶点， 可以加速对这种毁灭性儿科疾病的临床转化。