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DNA Repair, Cell Cycle Checkpoints and Apoptosis as Targets for Anticancer Drugs

DNA 修复、细胞周期检查点和细胞凋亡作为抗癌药物的靶点

基本信息

批准号：
7732906
负责人：
YVES POMMIER
金额：
$ 79.97万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7732906
关键词：
Accounting Antineoplastic Agents Apoptosis Apoptotic Arsenic Trioxide Ataxia Telangiectasia Base Excision Repairs Binding Biological Markers Camptothecin Cell Cycle Cell Cycle Checkpoint Cell Cycle Progression Cell Line Cells Cellular Assay Chromatin Clinic Clinical Clinical Trials Collaborations Complex Cyclin-Dependent Kinase Inhibitor Cyclins Cytokeratin DNA DNA Damage DNA Double Strand Break DNA Repair Databases Defect Development Developmental Therapeutics Program Enzymes Etoposide Europe Event Family Genetic Transcription Genomics Goals Guanine Knowledge Lesion Malignant Neoplasms Maps Measures Mediating Methodology Microfilaments Minor Groove Modification Molecular Monitor Nuclear Oligonucleotides Paclitaxel Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Pharmacology Phosphorylation Platinum Play RNA Recombinant Proteins Recombinants Reporting Role Sampling Scaffolding Protein Screening procedure Stimulus TDP-1 TNFSF10 gene TP53 gene Therapeutic Threonine Tissues Topoisomerase Topoisomerase Inhibitors Translating Translations Type I DNA Topoisomerases Work XRCC1 gene Xeroderma Pigmentosum adduct analog cancer cell chemotherapeutic agent crosslink high throughput screening human H2AX protein human TOP1 protein inhibitor/antagonist novel novel therapeutics pre-clinical programs repaired response sarcoma scaffold sulfotransferase tumor tyrosyl-DNA phosphodiesterase

项目摘要

Because most cancers have alterations in the cell cycle checkpoint pathways (p53, pRb) and cell cycle machinery (cyclins, cyclin-dependent kinase inhibitors such as p16), we are exploring inhibitors of cell cycle checkpoints as novel anticancer agents. We are investigating the role of Chk2 in cell cycle checkpoint response in cancer cells. We have expressed Chk2 as a recombinant protein and set up a high throughput screen to discover Chk2 inhibitors (collaboration with Drs. Shoemaker and Scudiero, DTP, NCI). We have discovered a novel family of Chk2 inhibitors, the bis-guanidylhydrazones and shown they act as competitive ATP inhibitors against Chk2. Analogs have been synthesized and selected. Cellular assays are being developed to measure Chk2 inhibition in cells and to determine whether Chk2 inhibitors can be used to synergize with Top1 inhibitors and other currently available chemotherapeutic agents. It is also well established that DNA repair defects predispose to cancers (for instance Xeroderma Pigmentosum and ataxia telangiectasia) and may play an important role in the response of cancers to treatments that target DNA and chromatin. We have set up high-throughput screens for inhibitors of tyrosyl-DNA phosphodiesterase (Tdp1), an enzyme of the base excision repair (BER) pathways involved in the repair of topoisomerase-mediated DNA damage. We have identified the first Tdp1 inhibitors, and we are searching for new inhibitors with therapeutic potential. Tdp1 inhibitors should be synergistic in combination with Top1 inhibitors. We are studying several new drugs in preclinical and early clinical development including agents from the NCI-Developmental Therapeutics Program (DTP). We are focusing on drugs that alter chromatin and cell cycle progression such as aminoflavone. Aminoflavone is beginning clinical trials and we found that aminoflavone induces replication double-strand breaks and histone H2AX phosphorylation (gamma-H2AX). Hence, gamma-H2AX can be used as a biomarker to monitor aminoflavone activity in tumor samples. Using the NCI 60 cell line database we found that sulfotransferase expression is highly correlated with aminoflavone activity and can be used to select patients who should benefit from aminoflavone. More recently, we found that aminoflavone mediates crosslinking between cytokeratins and RNA. This study suggests the possibility that cytokeratins (which constitute a major component of the cellular microfilament network) could serve as a scaffold for cytoplasmic RNA and potentially for translation. We have continued our studies on the molecular pharmacology of trabectedin, which has recently been approved for the treatment soft tissue sarcomas in Europe. We previously found that trabectedin differs from other clinically used anticancer agents because it forms covalent adducts at specific guanines in the DNA minor groove and because it selectively traps the transcription-coupled NER (TC-NER). We have now found that gamma-H2AX could serve as a pharmacodynamic biomarker for trabectedin. The activation of gamma-H2AX led us to show that the trapping of TC-NER by trabectedin induces the formation of Mre11- and transcription-dependent DNA double-strand breaks. Our studies on apoptosis are focused on chromatin modifications. We found that one of the early events in apoptosis is the induction of apoptotic Top1-DNA complexes. The apoptotic Top1-DNA complexes are induced by a variety of apoptotic stimuli: arsenic trioxide, etoposide, camptothecin, platinum derivatives, taxol, and vinblastin. Our working hypothesis that these apoptotic Top1-DNA complexes are produced by oxidative lesion of genomic DNA, which trap Top1 bound to chromatin. Apoptotic Top1-DNA complexes in turn activate additional apoptotic responses/pathways and might represent an irreversible apoptotic activation loop. To further elucidate the molecular events induced by the apoptotic program, we are focusing on nuclear alterations produced by TRAIL, which is in clinical trials.

因为大多数癌症都有细胞周期检查点通路（p53，pRb）的改变，和细胞周期机制（细胞周期蛋白，细胞周期蛋白依赖性激酶抑制剂，如p16），我们探索细胞周期检查点的抑制剂作为新的抗癌剂。我们研究Chk 2在癌细胞中细胞周期检查点应答中的作用。我们有以重组蛋白的形式表达Chk 2，并建立了高通量筛选Chk 2的方法抑制剂（与Shoemaker和Scudiero博士合作，DTP，NCI）。我们已经发现了一种 Chk 2抑制剂的新家族，双胍基腙，并显示它们作为竞争性 Chk 2的ATP抑制剂。合成并筛选了类似物。细胞分析是正在开发用于测量细胞中的Chk 2抑制并确定Chk 2抑制剂是否可用于与Top1抑制剂和其它目前可用的化疗药物协同作用剂. DNA修复缺陷易患癌症也是公认的（对于例如着色性干皮病和共济失调毛细血管扩张症），并可能在癌症对靶向DNA和染色质治疗的反应。我们成立高通量筛选酪氨酰-DNA磷酸二酯酶（Tdp 1）的抑制剂，碱基切除修复（BER）途径参与拓扑异构酶介导的DNA修复损害我们已经鉴定了第一个Tdp 1抑制剂，我们正在寻找新的抑制剂具有治疗潜力Tdp 1抑制剂与Top1组合应具有协同作用抑制剂的我们正在研究几种处于临床前和早期临床开发阶段的新药包括来自NCI-Developmental Therapeutics Program（DTP）的代理人。我们专注于改变染色质和细胞周期进程的药物，如氨甲喋呤。氨基酮是开始临床试验时，我们发现氨甲喋呤能诱导复制双链断裂和组蛋白H2 AX磷酸化（γ-H2 AX）。因此，γ-H2 AX可以用作用于监测肿瘤样品中的氨基甲酮活性的生物标志物。使用NCI 60细胞系数据库中，我们发现磺基转移酶的表达与氨基糖苷酮高度相关，活性，并可用于选择应受益于aminorone的患者。更最近，我们发现氨基异黄酮介导细胞角蛋白和RNA之间的交联。这一项研究表明，细胞角蛋白（构成细胞角蛋白的主要成分）细胞微丝网络）可以作为细胞质RNA的支架，翻译。我们继续对曲贝替丁的分子药理学进行研究，其最近在欧洲被批准用于治疗软组织肉瘤。我们先前发现曲贝替丁不同于其他临床使用的抗癌剂，它在DNA小沟中的特定鸟嘌呤上形成共价加合物，选择性捕获转录偶联NER（TC-NER）。我们现在发现γ-H2 AX 可作为曲贝替定的药效学生物标志物。γ-H2 AX的激活导致我们表明，Trabectedin对TC-NER的捕获诱导了Mre 11-和转录依赖的DNA双链断裂。我们对细胞凋亡的研究主要集中在染色质修饰我们发现细胞凋亡的早期事件之一是诱导凋亡Top1-DNA复合物。凋亡的Top1-DNA复合物是由多种凋亡刺激物：三氧化二砷、依托泊苷、喜树碱、铂衍生物、紫杉醇和长春新碱我们的工作假设是，这些凋亡的Top1-DNA复合物是由基因组DNA的氧化损伤，其捕获与染色质结合的Top1。凋亡Top1-DNA 复合物反过来激活额外的凋亡反应/途径，并可能代表一种不可逆凋亡激活环。为了进一步阐明由在凋亡程序中，我们关注的是由TRAIL产生的核改变，临床试验

项目成果

期刊论文数量（36）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effects of acetylation, polymerase phosphorylation, and DNA unwinding in glucocorticoid receptor transactivation.

乙酰化、聚合酶磷酸化和 DNA 解旋对糖皮质激素受体反式激活的影响。

DOI：
10.1016/j.jsbmb.2006.03.003
发表时间：
2006
期刊：
The Journal of steroid biochemistry and molecular biology
影响因子：
0
作者：
Kim,Yuli;Sun,Yunguang;Chow,Carson;Pommier,YvesG;SimonsJr,SStoney
通讯作者：
SimonsJr,SStoney

Molecular interaction maps--a diagrammatic graphical language for bioregulatory networks.

DOI：
10.1126/stke.2222004pe8
发表时间：
2004-02-24
期刊：
Science's STKE : signal transduction knowledge environment
影响因子：
0
作者：
Aladjem, Mirit I;Pasa, Stefania;Kohn, Kurt W
通讯作者：
Kohn, Kurt W

Abrogation of Chk1-mediated S/G2 checkpoint by UCN-01 enhances ara-C-induced cytotoxicity in human colon cancer cells.

DOI：
发表时间：
2004-06
期刊：
Acta pharmacologica Sinica
影响因子：
8.2
作者：
R. Shao;C. Cao;Y. Pommier
通讯作者：
R. Shao;C. Cao;Y. Pommier

In vitro evaluation of dimethane sulfonate analogues with potential alkylating activity and selective renal cell carcinoma cytotoxicity.

DOI：
发表时间：
2004-07
期刊：
Molecular cancer therapeutics
影响因子：
5.7
作者：
S. Mertins;T. Myers;S. Holbeck;Wilma Y. Medina-Pérez;E. Wang;G. Kohlhagen;Y. Pommier;S. Bates
通讯作者：
S. Mertins;T. Myers;S. Holbeck;Wilma Y. Medina-Pérez;E. Wang;G. Kohlhagen;Y. Pommier;S. Bates

[Cell cycle and checkpoints in oncology: new therapeutic targets]

[肿瘤学中的细胞周期和检查点：新的治疗靶点]