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KDM1A inhibitors as novel therapeutics for glioblastoma

KDM1A 抑制剂作为胶质母细胞瘤的新疗法

基本信息

批准号：
10576827
负责人：
Gangadhara R Sareddy
金额：
$ 29.36万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10576827
关键词：
Adjuvant Chemotherapy Affect Apoptosis Attenuated Binding Biochemical CRISPR/Cas technology Cell Therapy Cells ChIP-seq Chemotherapy and/or radiation Clinical Combined Modality Therapy Development Disease Environment Enzymes Epigenetic Process Excision External Beam Radiation Therapy Gene Expression Genes Glioblastoma Glioma Hypoxia Investments KDM1A gene Knowledge Lysine Maintenance Malignant - descriptor Mass Spectrum Analysis Mediating Metabolism Modeling Oncogenic Operative Surgical Procedures Pathway interactions Patients Pharmacotherapy Play Primary Brain Neoplasms Proliferating Proteins Radiation therapy Relapse Reporting Research Resistance Role Signal Transduction Survival Rate Testing Therapeutic Agents Toxic effect Treatment Efficacy Tumor Angiogenesis Tumor Promotion Tumor Tissue angiogenesis chemotherapeutic agent chemotherapy clinically significant efficacy testing endoplasmic reticulum stress epigenetic therapy histone demethylase improved in vivo inhibitor innovation mouse model new therapeutic target novel novel drug class novel therapeutics overexpression preclinical study programs response self-renewal standard care standard of care stem cell function stem cell self renewal stem cell survival stem cells stemness targeted treatment temozolomide therapeutic evaluation therapy resistant traditional therapy transcriptome sequencing tumor tumor growth tumor progression tumorigenic

项目摘要

Glioblastomas (GBM) are the most common and deadliest primary brain tumors that remain an incurable disease. Although GBM respond initially to standard radiation and chemotherapy, tumor relapse and therapy resistance are major obstacles for GBM treatment. Glioma stem cells (GSCs) are highly tumorigenic, sustain tumor growth, promote tumor angiogenesis, and are implicated in the poor response to standard therapies. The lysine demethylase KDM1A is an enzyme that contributes to epigenetic changes; and recent studies reported that it is highly expressed in GBM and GSCs. The rationale for this study is based on our preliminary results demonstrating that KDM1A modulates GSCs stemness and differentiation by promoting epigenetic changes. The objective of this proposal is to elucidate the functional role of KDM1A and test a possible clinical strategy to eradicate GSCs employing KDM1A-specific inhibitors. Our central hypothesis is that KDM1A is essential for GSCs stemness, hypoxia responses, therapy resistance; targeting of GSCs with KDM1A specific inhibitors reduces the stemness, induce differentiation, apoptosis, and sensitize to chemotherapy and radiation treatment leading to improved therapeutic efficacy. Our group recently developed novel inhibitors NCL-1 and NCD-38 that specifically inhibits KDM1A. In this proposal, we will use these novel inhibitors and test the hypothesis using three specific aims. In Aim 1, we will define how KDM1A inhibitors promote differentiation and apoptosis of GSCs. In Aim 2, we will determine the role of KDM1A inhibition in hypoxia-induced stemness, angiogenesis, and therapy resistance. In Aim 3, we will test the therapeutic efficacy of the KDM1A inhibitors alone and in combination with current standard-of-care chemo and radiation therapy. These studies are clinically significant as they will establish the mechanisms of KDM1A signaling in GSCs, and test the therapeutic potential of KDM1A inhibitors in treating GBM. The proposed research is innovative because of novel KDM1A inhibitors; and due to new concepts that investigate the KDM1A role in unfolded protein response, hypoxic response and therapy resistance. Successful testing of aims will establish KDM1A inhibitors as a novel class of drugs for the treatment of GBM. Using KDM1A inhibitors as an epigenetic therapy to target GSCs would be a substantial departure from traditional therapy, and could transform the currently inadequate treatment options for GBM.

胶质母细胞瘤(GBM)是最常见和最致命的原发脑肿瘤，至今仍是无法治愈的疾病。虽然GBM最初对标准放疗和化疗有反应，但肿瘤复发和治疗耐药性是GBM治疗的主要障碍。胶质瘤干细胞(GSCs)具有高度的致瘤性、持续性肿瘤生长，促进肿瘤血管生成，与标准治疗的不良反应有关。这个赖氨酸去甲基酶KDM1a是一种有助于表观遗传变化的酶；最近的研究报告在GBM和GSC中高表达。这项研究的基本原理是基于我们的初步结果证明KDM1A通过促进表观遗传变化来调节GSCs的干性和分化。这项建议的目的是阐明KDM1a的功能作用，并测试可能的临床策略以根除使用KDM1A特异性抑制剂的GSCs。我们的中心假设是KDM1a对于 GSCs干性、低氧反应、治疗耐药性；KDM1A型特异性抑制剂靶向GSCs 减少干细胞数量，诱导分化，诱导细胞凋亡，并对化疗和放射治疗敏感。从而提高了治疗效果。我们小组最近开发了新型抑制剂NCL-1和NCD-38，特异性地抑制KDM1a。在这个提案中，我们将使用这些新的抑制剂，并使用以下方法验证假设三个具体目标。在目标1中，我们将确定KDM1A抑制剂如何促进GSCs的分化和凋亡。在目标2中，我们将确定KDM1A抑制在低氧诱导的干细胞、血管生成和治疗中的作用。抵抗。在目标3中，我们将测试KDM1a抑制剂单独和联合应用的疗效。目前的标准护理化疗和放射治疗。这些研究具有重要的临床意义。建立KDM1A在GSCs中的信号转导机制，并检测KDM1A抑制剂的治疗潜力在治疗基底膜方面。拟议的研究是创新的，因为新的KDM1A抑制剂；以及新的研究KDM1A在未折叠蛋白反应、低氧反应和治疗中的作用的概念抵抗。AIMS的成功测试将使KDM1a抑制剂成为治疗该疾病的一类新型药物是GBM的。使用KDM1a抑制剂作为表观遗传疗法来靶向GSCs将是与传统疗法，并可能改变目前治疗基底膜不足的选择。