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，最有效的胶质瘤治疗方法仍然是dna。 有害物质：辐射和烷基化试剂替莫唑胺和亚硝脲，如CCNU。在这个项目中 在前一个周期，我们发现错配修复缺陷(MMRD)是替莫唑胺耐药的常见来源； 与其他癌症不同的是，通过MMRD获得替莫唑胺耐药性的胶质瘤往往对 免疫检查点抑制。但他们经常会对CCNU做出回应。我们假设一个更全面的理解 对TMZ和CCNU的不同抗性机制将使1)提高对时间和方式的了解 使用这些药物，包括临床上有用的生物标志物，以及2)使用联合策略的优化 靶向和免疫疗法是在过去十年中发展起来的。 尽管已经做了大量的工作来了解CCNU如何损伤DNA，并检测基因和 对于修复这种损伤的途径，该领域对CCNU效应的变化缺乏统一的理解 具有不同DNA损伤反应(DDR)特征的胶质瘤，耐药性是如何产生的，以及 CCNU的作用与其他药物相互作用，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。因此，我们缺乏能够 准确指导临床医生对有反应、不知道最佳方案的患者开CCNU 涉及CCNU的联合治疗方法和临床实践差异很大。 我们建议对其基因组效应和潜在的治疗作用进行系统评估。 CCNU。我们建议的一个主要创新是我们采用系统的方法来评估CCNU对 癌症存活、增殖和基因组完整性：当单独使用或与替莫唑胺联合使用时， RT和靶向DNA损伤反应通路的试剂；以及跨多种DNA损伤反应 上下文。为此，我们将利用体内和体外模型和体外模型中超过250个胶质瘤的活组织生物库 跨治疗条件的功能基因组学和基因组表征的最新技术 和解甲返乡的背景。我们的目标是：目标1：测试假设MMRD基于对TMZ的抗性在 GBM对CCNU和RT相对敏感，可通过血浆无细胞DNA检测。目标2： 验证与CCNU诱导的ICL修复有关的蛋白质缺陷决定对 CCNU与攻克策略。目标3：检验故意操纵突变特征的假设 通过协调TMZ、CCNU、RT和DDR途径的抑制，克隆动力学可以增加 免疫治疗的有效性。DNA损伤剂仍然是治疗胶质瘤和其他所有疾病的最有效的药物 癌症，在不同的DDR背景下，对其单独和组合的影响的统一理解 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 生物标记物驱动的与新的DDR靶点的组合。

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.