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）在弥漫性固有的庞然神经胶质瘤（DIPG）中的作用对于防止治疗耐药性和肿瘤进展以及设计疗法至关重要每年诊断出的200-400个小儿DIPG患者的寿命可能会延长寿命。放疗仍然是护理的标准，但是100％患者的肿瘤会复发，导致患者沮丧生存8-11个月。超过250次临床试验未能移动这些数字。机理迫切需要进行研究才能了解CSC的潜在生物学及其驱动方式耐药性以开发创新的组合疗法，以改变自然 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会导致热抗性和驱动肿瘤进展。在机械研究中，我们建议表征表观遗传受调节的干性程序和干细胞生态位（AIM 1和2）作为潜在目标（AIM 3）小儿dipg。具体而言，在AIM 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同工型的调节，特别是ALDH1A3 和ALDH2通过H3 K27M突变，分别由小胶质细胞分泌的IL1β仔细地分泌使用等源性DIPG模型在体外和体内测定中设计。我们将定义特定的作用细胞分化，肿瘤起始和进展和免疫力。在AIM 2中，我们将评估ALDH+ CSC是否是原因治疗性抗性，并导致肿瘤进展。我们将调制表达疾病相关的ALDH同工型并评估是否可以恢复热敏感性。我们将表征治疗诱导的干细胞生态位和免疫进化的机制使用尖端技术，包括单细胞RNA测序（SCRNA-SEQ）和CYTOF。在AIM 3中，我们将以ALDH+ CSC为目标，以此作为预防肿瘤进展的耐药性。在临床前概念验证研究中，我们将瞄准ALDH（二硫仑）和PI3K/MTOR（GDC-- 0084），ALDH+ CSC的细胞固有信号，以增强护理标准的结果（放射疗法）并防止进展。因此，我们的研究将（1）确认CSC 呈现一种电阻机制，（2）提供了针对这些细胞的理由（3）解决对有效疗法的未满足的临床需求。总而言之，我们的建议将机械地解决ALDH+ CSC在治疗性耐药性和DIPG的肿瘤缓解，并提供可吸毒的靶标，这可以加速临床翻译，以抵抗这种毁灭性的小儿疾病。