Evolution of gliomas during treatment and resistance

项目摘要 尽管几十年来对靶向治疗的研究，神经胶质瘤最有效的治疗方法仍然是DNA 损伤剂：辐射和烷化剂替莫唑胺和硝脲如CCNU。在这个项目中， 前一周期，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获得替莫唑胺耐药的胶质瘤往往对MMRd没有反应。 免疫检查点抑制。但他们经常回应CCNU。我们假设更全面的了解 对TMZ和CCNU的不同耐药机制的研究将使1）更好地了解何时以及如何 使用这些试剂，包括临床上有用的生物标志物，和2）使用 在过去的十年里，有针对性的和免疫疗法得到了发展。 尽管已经做了大量的工作来了解CCNU如何损害DNA并检测基因， 由于参与修复这种损伤的途径，该领域对CCNU的影响如何变化缺乏统一的理解 在具有不同DNA损伤反应（DDR）特征的胶质瘤中，耐药性是如何产生的， CCNU的作用与其它试剂包括DNA损伤剂如替莫唑胺和放射相互作用， 以及靶向特定DDR功能和途径的治疗剂。因此，我们缺乏生物标志物， 准确地指导临床医生给可能有反应的患者开CCNU，不知道最佳治疗方案。 包括CCNU在内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的评估， CCNU。我们的建议的一个主要创新是我们采用系统的方法来评估环己亚硝脲对 癌症存活和增殖以及基因组完整性：当单独使用和与替莫唑胺联合使用时， RT和靶向DNA损伤反应途径的药物;以及各种DNA损伤反应 contexts.为此，我们将在体内和体外模型中利用超过250个胶质瘤的活组织生物库， 在治疗条件下进行功能基因组学和基因组表征的最新技术 DDR背景。我们的目的是：目的1：检验基于MMRd的TMZ耐药性在一个特定的时间范围内的假设。 GBM对CCNU和RT相对敏感，可通过血浆游离DNA检测。目标二： 检验参与CCNU诱导的ICL修复的蛋白质缺陷决定对CCNU的抗性的假设。 CCNU和克服策略。目的3：检验突变谱的有意操纵 通过协调TMZ，CCNU，RT和DDR途径抑制的克隆动力学可以增加 免疫治疗的有效性。DNA损伤剂仍然是神经胶质瘤和所有其他肿瘤中最有效的药物。 癌症，统一认识其影响，在隔离和组合在不同的复员方案的背景下 在这一建议将塑造这些药物在临床实践中的使用，并指导新的 生物标记驱动的组合与新颖的DDR目标。

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.