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

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.

项目摘要尽管对靶向治疗进行了数十年的研究，神经胶质瘤最有效的治疗方法仍然是 DNA 破坏剂：辐射和烷化剂替莫唑胺和亚硝脲，如本项目中的 CCNU。在上一个周期中，我们发现错配修复缺陷（MMRd）是替莫唑胺耐药的常见来源；与其他癌症不同，通过 MMRd 获得替莫唑胺耐药性的神经胶质瘤往往不会对但他们经常对 CCNU 做出反应，我们追求的是更全面的理解。对 TMZ 和 CCNU 的不同耐药机制的研究将有助于 1) 提高对何时以及如何耐药的了解使用这些药物，包括临床上有用的生物标志物，以及 2) 使用过去十年发展了靶向疗法和免疫疗法。尽管已经开展了大量工作来了解 CCNU 如何损伤 DNA 并检测基因和修复这种损伤所涉及的途径，该领域缺乏对 CCNU 效应如何变化的统一理解具有不同 DNA 损伤反应 (DDR) 特征的神经胶质瘤，耐药性是如何产生的，以及如何 CCNU 与其他药物相互作用的影响，包括 DNA 损伤剂（如替莫唑胺）和辐射，以及针对特定 DDR 功能和途径的治疗方法，因此我们缺乏能够实现这一目标的生物标志物。准确指导追随者向可能有反应但不知道最佳方案的患者开出 CCNU 处方涉及 CCNU 的联合治疗方法和临床实践差异很大。我们建议对基因组效应和潜在的治疗作用进行系统评估我们提案的一项重大创新是我们评估 CCNU 对影响的系统方法。癌症存活和增殖以及基因组完整性：单独使用或与替莫唑胺联合使用时， RT，以及针对 DNA 损伤反应途径的药物；以及跨多种 DNA 损伤反应的药物；为此，我们将利用包含 250 多个神经胶质瘤体内和体外模型的活体组织生物库。用于跨治疗条件的功能基因组学和基因组表征的最先进技术我们的目标是：目标 1：检验 MMRd 在一定范围内对 TMZ 产生耐药性的假设。 GBM 表明对 CCNU 和 RT 的相对敏感性，可以通过血浆游离 DNA 进行检测目标 2：检验以下假设：参与 CCNU 诱导 ICL 修复的蛋白质缺陷决定了对 ICL 的抵抗力 CCNU 和克服策略目标 3：检验有意操纵突变谱的假设。通过协调 TMZ、CCNU、RT 和 DDR 通路抑制可以增加克隆动力学 DNA 损伤剂仍然是治疗神经胶质瘤和所有其他疾病最有效的药物。癌症，对不同 DDR 环境中单独和组合的影响的统一理解该提案将塑造这些药物在临床实践中的使用，并指导新药物的开发生物标记驱动的与新型 DDR 靶标的组合。