Novel DNA damage response inhibitor and alkylator combinations for GBM

项目描述/摘要-项目1 烷基化化疗是新诊断疾病标准治疗的支柱部分， 并且它们也用于复发性设置。我们和其他人已经证明，这些代理人都诱导 独特的DNA损伤谱，它参与特定的DNA损伤反应（DDR）途径，这取决于 关键DNA修复途径的状态。最常用的药物是替莫唑胺（TMZ）， 诱导离散DNA碱基位点上的甲基加合物的单官能烷化剂，以及洛莫司汀和 卡莫司汀，它们是诱导单加合物和DNA交联的双功能烷化剂。不同 由这些和其他烷化剂治疗诱导的DNA损伤严重地触发了不同的DNA损伤反应 由共济失调-毛细血管扩张突变（ATM）和ATM/Rad 3相关（ATR）激酶调节，这些激酶协调了 细胞对广泛的遗传毒性损伤的反应。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），以评价多种高脑渗透性ATM和ATR抑制剂与放射的组合 治疗和烷基化化疗。我们的初步数据表明TMZ和 ATR抑制剂，特别是在GBM模型缺乏。机械性，未修复的O 6-甲基鸟嘌呤病变 TMZ诱导的复制应激和ATR信号轴的激活。相反，协同 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 烷基化损伤相对不受MGMT修复活性的影响。总的来说，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引发不同的 ATM和ATR控制的DNA损伤反应途径的功能和时间激活。 理解这些关系可用于定义ATR或ATM抑制剂与以下药物的最佳组合： 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.