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：
10475652
负责人：
Yilun Liu
金额：
$ 40.96万
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/10475652
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 Testing Therapeutic Treatment-Related Cancer antagonist cancer cell cancer therapy chemotherapy design experimental study in vivo inhibitor 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）A，A 独特的翻译后修饰，主要诱导DNA损伤。抑制parp 抑制剂消除了早期募集DNA损伤响应因素的招募，并会损害DNA损伤修复。由于荷脂是一种非常短暂的翻译后修饰，因此正常细胞具有其他修复弥补依赖dna损伤反应的损失的机制。但是，一组肿瘤细胞具有遗传突变，例如BRCA1/2突变，这些突变已经导致DSB受损维修。采用其他PARP抑制剂治疗以废除依赖性的DNA损伤反应，这些肿瘤细胞会发生凋亡。因此，PARP抑制剂治疗有选择地用DNA杀死肿瘤细胞损害修复缺陷，例如BRCA肿瘤。但是，最近的临床试验表明，只有一组BRCA肿瘤对PARP有效反应抑制剂治疗。此外，累积证据表明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，扩展了癌症治疗中的PARP抑制剂，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NAD+衍生物NADP+可以在体外和体内抑制PARP的活性。因此，我们假设NADP+是一种内源性PARP抑制剂，肿瘤细胞中的NADP+高水平是能够使肿瘤细胞用于DNA损害相关的癌症治疗，包括化学疗法和放疗治疗。在此应用中，我们计划检查1）NADP+在聚（ADP-核糖基）依赖性DNA中的作用损坏修复； 2）调节NADP+细胞水平的分子机制； 3）NADP+在将肿瘤细胞敏化对DNA损害相关的癌症治疗。综上所述，拟议的研究不仅会揭示DNA损伤修复中的新分子机制，还会揭示但还确定了新型的癌症治疗方法。