Evolution of gliomas during treatment and resistance

神经胶质瘤在治疗和耐药过程中的演变

基本信息

批准号：
10298648
负责人：
RAMEEN BEROUKHIM
金额：
$ 73.66万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10298648
关键词：
Address Adult Alkylating Agents Alkylation Amino Acids Biological Assay Biological Markers CHEK1 gene Carmustine Characteristics Clinical Trials Clonality Collection Combined Modality Therapy DNA Damage DNA Interstrand Crosslinking DNA Repair Data Defect Development Effectiveness Evaluation Evolution Generations Genes Genome Genomics Glioblastoma Glioma Grant Guanine Human Immune response Immunotherapy Induced Mutation Knowledge Lesion Light Lomustine MGMT gene Malignant - descriptor Malignant Glioma Malignant Neoplasms Mediating Methylation Mismatch Repair Mismatch Repair Deficiency Modeling Modernization Molecular Mutation New Agents Nitrosourea Compounds PD-1/PD-L1 PDL1 inhibitors Pathway interactions Patient Monitoring Patients Plasma Cells Primary Brain Neoplasms Proteins Radiation Radiation Tolerance Radiation induced damage Research Resistance Role Shapes Source Technology Testing Therapeutic Tissues Toxic effect United States Work base biobank biomarker-driven cancer survival cell free DNA checkpoint inhibition checkpoint therapy chemotherapy clinical biomarkers clinical implementation clinical practice crosslink effective therapy experimental study functional genomics genome integrity improved improved outcome in vitro Model in vivo inhibitor/antagonist innovation interest mouse model mutant neoantigens novel novel therapeutic intervention phase III trial predicting response prevent promoter radioresistant repaired resistance mechanism response targeted agent targeted treatment temozolomide therapeutic target therapy resistant treatment strategy tumor

Address Adult Alkylating Agents Alkylation Amino Acids Biological Assay Biological Markers CHEK1 gene Carmustine Characteristics Clinical Trials Clonality Collection Combined Modality Therapy DNA Damage DNA Interstrand Crosslinking DNA Repair Data Defect Development Effectiveness Evaluation Evolution Generations Genes Genome Genomics Glioblastoma Glioma Grant Guanine Human Immune response Immunotherapy Induced Mutation Knowledge Lesion Light Lomustine MGMT gene Malignant - descriptor Malignant Glioma Malignant Neoplasms Mediating Methylation Mismatch Repair Mismatch Repair Deficiency Modeling Modernization Molecular Mutation New Agents Nitrosourea Compounds PD-1/PD-L1 PDL1 inhibitors Pathway interactions Patient Monitoring Patients Plasma Cells Primary Brain Neoplasms Proteins Radiation Radiation Tolerance Radiation induced damage Research Resistance Role Shapes Source Technology Testing Therapeutic Tissues Toxic effect United States Work base biobank biomarker-driven cancer survival cell free DNA checkpoint inhibition checkpoint therapy chemotherapy clinical biomarkers clinical implementation clinical practice crosslink effective therapy experimental study functional genomics genome integrity improved improved outcome in vitro Model in vivo inhibitor/antagonist innovation interest mouse model mutant neoantigens novel novel therapeutic intervention phase III trial predicting response prevent promoter radioresistant repaired resistance mechanism response targeted agent targeted treatment temozolomide therapeutic target therapy resistant treatment strategy tumor

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项目摘要

Project Abstract Despite decades of research into targeted therapeutics, the most effective treatments in glioma remain DNA damaging agents: radiation and the alkylating agents temozolomide and nitrosureas like CCNU. In this project’s prior cycle, we found that mismatch repair deficiency (MMRd) is a common source of temozolomide resistance; and that unlike other cancers, gliomas that gain temozolomide resistance through MMRd tend not to respond to immune checkpoint inhibition. But they often do respond to CCNU. We hypothesize that a fuller understanding of the different resistance mechanisms to TMZ and CCNU will enable 1) improved knowledge of when and how to use these agents, including clinically useful biomarkers, and 2) optimization of combined strategies using targeted and immunotherapies developed over the last decade. Although extensive work has been done to understand how CCNU damages DNA and to detect genes and pathways involved in repairing this damage, the field lacks a unified understanding of how CCNU effects vary across gliomas with different DNA damage response (DDR) characteristics, how resistance arises, and how the effects of CCNU interact with other agents including DNA damaging agents such as temozolomide and radiation, as well as therapeutics targeting specific DDR functions and pathways. As a result, we lack biomarkers that can accurately guide clinicians to prescribe CCNU to patients who are likely to respond, do not know the optimal combined therapeutic approaches involving CCNU, and clinical practice varies widely. We propose to pursue a systematic evaluation of the genomic effects and potential therapeutic roles of CCNU. A major innovation in our proposal is our systematic approach to evaluating the effects of CCNU on cancer survival and proliferation and genome integrity: when used alone and in combination with temozolomide, RT, and agents targeting DNA damage response pathways; and across a wide variety of DNA damage response contexts. For this, we will leverage a living tissue biobank of over 250 gliomas in vivo and in vitro models and state-of-the-art technologies for functional genomics and genome characterization across treatment conditions and DDR backgrounds. Our Aims are: Aim 1: Test the hypothesis that MMRd based resistance to TMZ within a GBM indicates relative sensitivity to CCNU and RT and can be detected through plasma cell-free DNA. Aim 2: Test the hypothesis that defects in proteins involved in repair of CCNU-induced ICLs determine resistance to CCNU and strategies to overcome. Aim 3: Test the hypothesis that intentional manipulation of mutational profiles and clonal dynamics by coordinating TMZ, CCNU, RT, and DDR pathway inhibition can increase the effectiveness of immunotherapy. DNA damaging agents remain the most effective agents in glioma and all other cancers, the unified understanding of their effects in isolation and combination across the varied DDR contexts in this proposal will shape the use of these agents in clinical practice and guide the development of new biomarker-driven combinations with novel DDR targets.

项目摘要尽管对有针对性治疗进行了数十年的研究，但神经胶质瘤中最有效的疗法仍然是DNA 破坏性剂：辐射和烷基化剂替莫唑胺和硝基核酸酶（如CCNU）。在这个项目中先前的周期，我们发现不匹配修复缺陷（MMRD）是替莫唑胺抗性的常见来源。与其他癌症不同的是，通过MMRD获得替莫唑胺抗性的胶质瘤往往不反应免疫检查点抑制。但是他们经常对CCNU做出回应。我们假设这是一个更充分的理解在TMZ和CCNU的不同耐药机制中，将使1）提高对何时以及如何的了解使用这些药物，包括临床上有用的生物标志物，2）使用在过去的十年中，有针对性和免疫疗法发展。尽管已经完成了广泛的工作来了解CCNU如何损害DNA并检测基因和涉及修复这种损害的途径，该领域缺乏对CCNU效应如何变化的统一了解跨具有不同DNA损伤反应（DDR）特征的神经胶质瘤，如何产生抗性以及如何 CCNU的影响与其他药物相互作用，包括DNA损伤剂，例如替莫唑胺和辐射，以及针对特定DDR功能和途径的治疗。结果，我们缺乏可以准确地指导临床医生为可能有反应的患者准备CCNU，不知道最佳联合治疗方法涉及CCNU，临床实践差异很大。我们建议对基因组效应和潜在治疗作用进行系统评估 CCNU。我们的提案中的一个主要创新是我们的系统方法来评估CCNU的影响癌症的生存和增殖和基因组完整性：单独使用并与替莫唑胺结合使用时， RT和针对DNA损伤响应途径的试剂；并跨越多种DNA损伤响应上下文。为此，我们将利用体内和体外模型超过250个神经胶质瘤的活组织生物库以及在治疗条件上进行功能基因组学和基因组表征的最新技术和DDR背景。我们的目标是：目标1：检验以下假设： GBM表示对CCNU和RT的相对敏感性，可以通过无等离子体细胞的DNA检测。目标2：检验以下假设：涉及CCNU诱导的ICL的蛋白质缺陷确定对 CCNU和克服策略。目标3：检验有意操纵突变曲线的假设通过协调的TMZ，CCNU，RT和DDR途径可以增加抑制作用和克隆动力学免疫疗法的有效性。 DNA损伤剂仍然是神经胶质瘤和所有其他所有其他药物的最有效药物癌症，统一对它们效果的统一理解在不同的DDR环境中孤立和组合在此提案中，将塑造这些代理在临床实践中的使用，并指导新的新型DDR靶标生物标志物驱动的组合。