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

基本信息

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
项目类别：
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

项目摘要

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) 在弥漫性内在桥脑胶质瘤 (DIPG) 中的作用是对于预防治疗耐药性和肿瘤进展以及设计治疗方法至关重要每年可延长 200-400 名接受放射治疗的儿童 DIPG 患者的生命。仍然是护理标准，但 100% 的患者肿瘤会复发，导致患者情绪低落超过 250 项临床试验未能改变这些数字。迫切需要研究来了解 CSC 的基础生物学及其驱动方式治疗耐药性开发创新的组合疗法，可以改变自然 DIPG 的丰富历史和现有文献支持了总体观点。假设乙醛氢化酶阳性 (ALDH+) CSC 导致治疗抵抗和我们建议，在机制研究中，从表观遗传学角度来表征。受监管的干性计划和干细胞生态位（目标 1 和 2）作为潜在目标（目标 3）具体而言，在目标 1 中，我们将确定 ALDH 阳性的作用和调节。我们将评估 DIPG 中的 CSC 对特定 ALDH 亚型的调节，特别是 ALDH1A3。和 ALDH2 分别由 H3 K27M 突变和小胶质细胞分泌的 IL1β 引起，仔细地使用同基因 DIPG 模型设计体外和体内测定，我们将定义特定的作用。 ALDH 亚型，包括 ALDH1A3 和 ALDH2，在细胞分化、肿瘤发生和在目标进展和免疫中，我们将评估 ALDH+ CSC 是否是导致疾病的原因。我们将调节治疗耐药性并负责肿瘤进展。疾病相关的 ALDH 亚型以及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拥有尖端技术，包括单细胞 RNA 测序 (scRNA-seq) 和 CyTOF。在目标 3 中，我们将把 ALDH+ CSCs 作为抵抗的原因，以防止肿瘤进展。在临床前概念验证研究中，我们将针对 ALDH（双硫仑）和 PI3K/mTOR（GDC- 0084)，ALDH+ CSC 的细胞内在信号传导，可增强护理标准的结果（放射治疗）并预防进展因此，我们的研究将（1）证实 CSC。提出耐药机制并 (2) 提供专门针对这些细胞的基本原理 (3) 解决尚未满足的有效疗法的临床需求。总之，我们的提案将机械地解决 ALDH+ CSC 在 DIPG 的治疗耐药性和肿瘤复发并提供可药物靶点，可以加速针对这种毁灭性儿科疾病的临床转化。