Ionizing Radiation-Induced DNA damage repair

电离辐射诱导的 DNA 损伤修复

基本信息

批准号：
10237352
负责人：
Yilun Liu
金额：
$ 41.8万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10237352
关键词：
Apoptosis BRCA mutations BRCA1 Mutation BRCA2 Mutation Back Biological Markers Cell Cycle Arrest Cell Cycle Progression Cells Chemical Structure Chemotherapy and/or radiation Clinical Research Clinical Treatment Clinical Trials DNA DNA Damage DNA Double Strand Break DNA Repair DNA Sequence Alteration Defect Double Strand Break Repair FDA approved Growth Impairment In Vitro Ionizing radiation Lead Lesion Malignant Neoplasms Malignant neoplasm of ovary Mediating Molecular NAD+ kinase NADP Normal Cell Phosphoric Monoester Hydrolases Phosphorylation Post-Translational Protein Processing Radiation induced double strand break Radiation therapy Regulation Research Project Grants Role Signal Transduction Structure Testing Therapeutic Treatment-Related Cancer cancer cell cancer therapy chemotherapy design experimental study in vivo inhibitor/antagonist neoplastic cell novel novel therapeutic intervention ovarian neoplasm potential biomarker recruit repaired response sensor triple-negative invasive breast carcinoma tumor tumor DNA

项目摘要

PARP inhibitors have been used in the clinical treatment for tumors with BRCA1 or BRCA2 mutations. The major function of PARP inhibitors is to suppress PARP1 and PARP2 mediated poly(ADP-ribosyl)ation, a unique posttranslational modification, mainly induced in DNA damage. Suppression of PARylation by PARP inhibitors abolishes early recruitment of DNA damage response factors and impairs DNA damage repair. Because PARylation is a very transient posttranslational modification, normal cells have other repair mechanism to compensate for the loss of PARylation-dependent DNA damage response. However, a set of tumor cells harbor genetic mutations, such as BRCA1/2 mutations, which have already led to impaired DSB repair. With additional PARP inhibitor treatment to abolish PARylation-dependent DNA damage response, these tumor cells will undergo apoptosis. Thus, PARP inhibitor treatment selectively kills tumor cells with DNA damage repair defects, such as BRCA tumors. However, recent clinical trials suggest that only a set of BRCA tumors respond effectively to the PARP inhibitor treatment. Moreover, accumulated evidence indicates that PARP inhibitor treatment is able to suppress the growth of other types of tumor besides BRCA tumors. Thus, to extend the therapeutic potential of PARP inhibitors in cancer treatment, we explored biomarkers for the PARP inhibitor treatment. Interestingly, we found that NADP+, an NAD+ derivative, can suppress the activity of PARPs both in vitro and in vivo. Thus, we hypothesize that NADP+ is an endogenous PARP inhibitor, and the high level of NADP+ in tumor cells is able to sensitize tumor cells for DNA damaging related cancer therapy, including chemotherapy and radiation therapy. In this application, we plan to examine 1) the role of NADP+ in poly(ADP-ribosyl)ation-dependent DNA damage repair; 2) the molecular mechanism that regulates the cellular level of NADP+; 3) the role of NADP+ in sensitizing tumor cells to DNA damaging-associated cancer therapy. Taken together, the proposed study will not only reveal novel molecular mechanism in DNA damage repair, but also identify novel therapeutic approach for cancer treatment.

PARP抑制剂已用于临床治疗具有BRCA1或BRCA2突变的肿瘤。这 PARP 抑制剂的主要功能是抑制 PARP1 和 PARP2 介导的聚（ADP-核糖基）化，独特的翻译后修饰，主要诱导DNA损伤。 PARP 抑制 PARylation 抑制剂消除了 DNA 损伤反应因子的早期募集并损害 DNA 损伤修复。由于 PARylation 是一种非常短暂的翻译后修饰，正常细胞还有其他修复补偿 PARylation 依赖性 DNA 损伤反应损失的机制。然而，一组肿瘤细胞含有基因突变，例如 BRCA1/2 突变，这些突变已经导致 DSB 受损维修。通过额外的 PARP 抑制剂治疗来消除 PARylation 依赖性 DNA 损伤反应，这些肿瘤细胞将发生凋亡。因此，PARP抑制剂治疗可选择性杀死带有DNA的肿瘤细胞损伤修复缺陷，例如 BRCA 肿瘤。然而，最近的临床试验表明，只有一组 BRCA 肿瘤对 PARP 有效应答抑制剂治疗。此外，积累的证据表明 PARP 抑制剂治疗能够抑制除 BRCA 肿瘤以外的其他类型肿瘤的生长。因此，为了扩大治疗潜力 PARP 抑制剂在癌症治疗中的应用，我们探索了 PARP 抑制剂治疗的生物标志物。有趣的是，我们发现NADP+，一种NAD+衍生物，可以在体外和体内抑制PARPs的活性。因此，我们假设NADP+是一种内源性PARP抑制剂，肿瘤细胞中高水平的NADP+是能够使肿瘤细胞对 DNA 损伤相关的癌症治疗敏感，包括化疗和放疗治疗。在此应用中，我们计划研究 1) NADP+ 在聚（ADP-核糖基）化依赖性 DNA 中的作用损坏修复； 2）调节细胞NADP+水平的分子机制； 3）NADP+的作用使肿瘤细胞对 DNA 损伤相关的癌症治疗敏感。总而言之，这项研究不仅将揭示 DNA 损伤修复的新分子机制，还确定了癌症治疗的新治疗方法。