Targeting Transcriptional Elongation in Pediatric Glioma

靶向小儿胶质瘤的转录延伸

基本信息

批准号：
10829524
负责人：
Rintaro Hashizume
金额：
$ 37.81万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10829524
关键词：
Acetylation Animals Astrocytes Biological Brain CRISPR/Cas technology Cancer Patient Cells ChIP-seq Characteristics Child Childhood Brain Neoplasm Childhood Glioma Chromatin Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Combined Modality Therapy Complex DNA Damage DNA Repair DNA Repair Pathway Data Dependence Development Diagnosis Diffuse intrinsic pontine glioma Disease Drug Kinetics Elongation Factor Epigenetic Process Expression Profiling Foundations Gene Expression Gene Mutation Genes Genetic Genetic Screening Genetic Transcription Goals Growth Histone H3 Histones Human In Vitro Individual Knock-out Knowledge Lysine Malignant Childhood Neoplasm Mediating Methionine Methylation Mission Modeling Modification Molecular Mutation National Institute of Neurological Disorders and Stroke Nature Nervous System Oncogenic Pathogenesis Patient-Focused Outcomes Patients Polymerase Positive Transcriptional Elongation Factor B Property Public Health RNA RNA Polymerase II Radiation Radiation Tolerance Radiation enhancer Radiation therapy Rare Diseases Research Resistance Sequence Analysis Tertiary Protein Structure Testing Therapeutic Therapeutic Intervention Toxic effect Transcription Elongation Transcription Initiation Transcriptional Activation Treatment outcome Xenograft procedure bioluminescence imaging chemotherapeutic agent clinical practice combinatorial early phase clinical trial effective therapy experimental study genome-wide improved in vivo inhibitor inhibitor therapy knock-down mutant neoplastic cell nervous system disorder new therapeutic target novel novel therapeutic intervention patient derived xenograft model patient screening pharmacologic prevent protein H(3)research clinical testing small hairpin RNA small molecule small molecule inhibitor targeted treatment therapeutic target therapeutically effective therapy resistant transcriptional reprogramming transcriptome transcriptome sequencing tumor tumor growth tumor progression

项目摘要

PROJECT SUMMARY/ABSTRACT - Diffuse intrinsic pontine glioma (DIPG) is one of the most devastating pediatric cancers. Numerous clinical trials in decades, involving different combinations of chemotherapeutic agents and radiation, have been ineffective in treating DIPG. The identification of efficacious therapeutic targets based on the molecular characteristic is of high importance for improving treatment outcomes for children with DIPG. The discovery of oncogenic histone gene mutations in DIPG has dramatically improved our understanding of disease pathogenesis, and stimulated the development of novel therapeutic approaches to target epigenetic modifiers. We have recently shown that targeted bromo- and extra-terminal (BET) domain protein 4 (BRD4) activity using JQ1 inhibitor results in a significant delay of tumor progression and prolonged survival of animals bearing DIPG patient-derived xenograft (PDX). Because of their promising anti-tumor activity, BRD4 inhibitors are being tested in a number of cancer patient clinical trials. However, tumors that initially respond to small molecule inhibitor therapies, such as those targeting BRD4 activity, eventually become resistant to monotherapy treatment, affirming the need for more effective therapeutic interventions. In order to identify new effective therapeutic targets, and discover novel combinatorial approaches to prevent or delay acquired resistance to monotherapy, we performed an unbiased genome-wide CRISPR/Cas9-based genetic screen of patient-derived DIPG cells. We identified nine “network modules” that are significantly enriched in CRISPR targets. One of these modules includes POLR2I, which encodes a subunit of RNA polymerase II (Pol II) that is involved in transcription elongation. We subsequently observed that targeting POLR2I activity through short-hairpin RNA knockdown and treatment of the small-molecule Pol II inhibitors block transcriptional elongation and inhibit the growth of DIPG in vitro and in vivo. Here, we will test the hypothesis that inhibition of Pol II transcriptional elongation in combination with BRD4 inhibition will further suppress gene transcription and will either delay or prevent DIPG from acquiring resistance to monotherapy. This dual inhibition approach will interfere with gene transcription at two levels: transcriptional initiation (BRD4) and elongation (Pol II). This project will also explore how these targeted therapies interact with radiation in treating DIPG, which is important due to the use of radiation in treating nearly all cases of DIPG in children. The successful completion of proposal study has significant impact on clinical practice and accumulating data from this research could therefore lay the foundation for early clinical trials of this approach, given the high unmet need and orphan disease status of DIPG.

项目摘要/摘要-Diffuse固有的蓬托神经胶质瘤（DIPG）是最令人震惊的小儿癌症。药物和辐射无效地处理DIPG。基于分子特征，与with with with with with with with。 DIPG。疾病发病机理，并激发了新型治疗方法的发展修改器。使用JQ1抑制剂的活性导致肿瘤进展的显着延迟和动物的长期存活率轴承DIPG患者衍生异种移植（PDX）。在许多癌症患者临床试验中进行了测试。分子抑制剂疗法，例如针对BRD4活性的分子疗法，最终对单一疗法具有抗性治疗，确认需要更多更多的治疗性介入。治疗靶标，并发现新颖的新型组合方法，以防止或延迟获得的抵抗力单一疗法，我们进行了公正的全基因组CRISPR/CAS9的基于患者衍生的遗传筛查 DIPG细胞。模块包括Polr2i，该模块编码RNA聚合酶II的亚基（POLII）伸长。我们随后观察到polr2i活动剧院小分子pol II的治疗吸入器阻断转录伸长并抑制DIPG的生长在体内和体内，我们将测试抑制POL II转录的假设与BRD4抑制的结合将进一步抑制基因转录，并将延迟或证明的DIPG 从获得抗性到单一疗法。两个级别：转录启动（BRD4）和伸长率（POL II）。靶向疗法在治疗DIPG时与辐射相互作用，这很重要。几乎所有在儿童中的DIPG病例。临床实践和从研究中积累数据可能是临床的基础鉴于DIPG的高度统一需求和孤儿疾病状况，这种方法的试验。