Novel DNA damage response inhibitor and alkylator combinations for GBM

项目说明/摘要-项目1 烷化化疗是新诊断疾病标准治疗的一部分， 同时，它们也被用在复现场景中。我们和其他人已经证明了这些药物都能诱导 DNA损伤的独特光谱，它涉及特定的DNA损伤反应(DDR)途径，取决于 关键的DNA修复途径的状态。最常用的药物是替莫唑胺(TMZ)， 在离散的DNA碱基上诱导甲基加合物的单官能性烷化剂，以及洛莫司汀和 卡莫司汀是一种双官能化烷基化物，可诱导单加合物和DNA交联物。不同的 这些和其他烷基化疗法引起的DNA损伤会引发不同的DNA损伤反应 由共济失调-毛细血管扩张突变(ATM)和ATM/RAD3相关(ATR)激酶调节，它们协调 细胞对一系列基因毒性侮辱的反应。在过去的几年里，我们与 NCI癌症治疗评估计划和多家制药公司(阿斯利康、Vertex、默克 KGaA，Bayer)评估多种高脑渗透性ATM和ATR抑制剂与放射的结合 治疗和烷化化疗。我们的初步数据显示TMZ和TMZ之间存在强大的协同效应 ATR抑制剂，特别是在GBM模型中缺乏。机械上，未修复的O6-甲基鸟嘌呤损伤 TMZ诱导复制应激，激活ATR信号轴。相比之下，协同效应 ATR抑制剂与洛莫司汀的相互作用与MGMT状态无关，这反映了一组不同的 相对不受MGMT修复活性影响的烷基化损伤。总体而言，我们广泛的初步数据 支持基本的科学前提，即单功能和双功能烷化剂疗法会引发不同的 ATM和ATR控制的DNA损伤反应通路的功能和时间激活。 了解这些关系可以用来定义ATR或ATM抑制剂的最佳组合 用于GBM的各种烷化剂。

PROJECT DESCRIPTION/ABSTRACT – PROJECT 1 Alkylating chemotherapies are part of the backbone of standard-of-care therapy in newly diagnosed disease, and they are also used in the recurrent setting. We and others have demonstrated that these agents each induce unique spectra of DNA damage, which engage specific DNA damage response (DDR) pathways depending on the status of key DNA repair pathways. The most commonly used agents are temozolomide (TMZ), a monofunctional alkylator that induces methyl-adducts on discrete DNA base sites, and lomustine and carmustine, which are bifunctional alkylators that induce both mono-adducts and DNA cross-links. The different DNA lesions induced by these and other alkylating therapies trigger distinct DNA damage responses critically modulated by ataxia-telangiectasia mutated (ATM) and ATM/Rad3-related (ATR) kinases, which orchestrate the cellular response to a broad array of genotoxic insults. Over the past few years, we have collaborated with the NCI Cancer Therapy Evaluation Program and multiple pharmaceutical companies (AstraZeneca, Vertex, Merck KGaA, Bayer) to evaluate multiple highly brain penetrant ATM and ATR inhibitors in combination with radiation therapy and alkylating chemotherapies. Our preliminary data demonstrate robust synergy between TMZ and ATR inhibitors, specifically in GBM models lacking. Mechanistically, unrepaired O6-methyguanine lesions induced by TMZ cause replication stress and activation of the ATR signaling axis. In contrast, synergistic interactions of ATR inhibitors with lomustine were independent of MGMT status, which reflects a distinct set of alkylation lesions that are relatively unaffected by MGMT repair activity. Overall, our extensive preliminary data support the fundamental scientific premise that monofunctional and bifunctional alkylator therapies trigger distinct functional and temporal activation of DNA damage response pathways governed by ATM and ATR. Understanding these relationships can be used to define optimal combinations of ATR or ATM inhibitors with various alkylating agents for GBM.