Biomarkers, mechanisms and modulation of oxidative stress associated risk factors in carcinogenesis

致癌过程中氧化应激相关危险因素的生物标志物、机制和调节

基本信息

批准号：
10704632
负责人：
Yun Rose Li
金额：
$ 42.26万
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：
2022
资助国家：
美国
起止时间：
2022-09-14 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10704632
关键词：
Acute Adverse event Aging Algorithms Animal Model Animals Appointment Architecture Binding Binding Sites Biological Biological Assay Biological Markers CCCTC-binding factor Caloric Restriction Cancer Biology Cancer Patient Carcinogen exposure Carcinogens Cause of Death Cell Cycle Regulation Cell Line Cells ChIP-seq Chromatin Chronic Cities Clinical Clinical Data Clonal Expansion Colorectal Colorectal Cancer Colorectal Neoplasms Computational Biology Computational Technique DNA Damage DNA Repair DNA Sequence Alteration Data Dedications Defect Developed Countries Developing Countries Development Diet Disease Energy Intake Epidemiology Epigenetic Process Exercise Exposure to Extramural Activities Faculty Fasting Feces Funding Future Genes Genetic Genomics Growth High School Student Human Incidence Individual Induced Mutation Induction of Apoptosis Inflammation Inflammatory Institution Intake Intermittent fasting International Joints Journals Laboratories Lead Leadership Life Style Link Location Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Malignant neoplasm of prostate Mathematics Meat Mediating Medicine Mentors Mentorship Metabolic Molecular Molecular Biology Molecular Computations Molecular Epidemiology Mutagenesis Mutagens Mutation Normal Cell Normal tissue morphology Obesity Outcome Oxidative Stress Patients Pattern Peer Review Pelvis Peripheral Blood Mononuclear Cell Personal Satisfaction Phase I/II Trial Physicians Positioning Attribute Postdoctoral Fellow Predisposition Probability Process Publications Quality of life Radiation Radiation Oncology Radiation therapy Randomized Reactive Oxygen Species Rectal Cancer Reporting Research Risk Factors Safety Science Scientist Smoking Societies Somatic Mutation TP53 gene Testing Therapeutic Therapeutic Index Time Tissues Toxic effect Translating Treatment-related toxicity Ultraviolet Rays Unhealthy Diet Urine Urothelial Cell Work cancer cell cancer genome cancer initiation cancer risk carcinogenesis career career networking chronic inflammatory disease clinical translation cohort colon cancer patients computerized tools cytokine dietary driver mutation epigenomics experience genome sequencing improved induced pluripotent stem cell lifestyle data lifestyle factors modifiable risk multidisciplinary multiple omics novel obesity genetics phase 3 study pre-clinical primary endpoint professor promoter prospective repaired side effect tool transcriptome sequencing tumor tumorigenesis whole genome

项目摘要

Abstract Cancer is the second most common cause of death in developed nations, and incidence is rising among developing nations. An estimated 70% of cancers are attributable to “modifiable” risk factors, including obesity, chronic inflammatory diseases, and poor diet, all of which have been associated with increased oxidative stress. These are not themselves “carcinogenetic”, but they are thought to act as “cancer promoters”, increasing the probability of developing cancer. With advances in whole genome sequencing and development of computational techniques to examine the cancer genome, we can now use mathematical profiling of somatic mutational profiles (termed mutational signatures) to identify potential causes underlying a given tumor (e.g., smoking versus UV light). It remains unclear, however, if there is a mutational signature that is a biomarker of cumulative lifetime exposure to reactive oxygen species (ROS)-mediated DNA damage and if this correlates with cancer-associated lifestyle factors. Here, we will utilize cutting-edge multi-omic profiling and molecular biology and computational tools to better understand the contribution/mechanism of oxidative stress as a cancer promoter. To examine the correlation of ROS mutational signature levels and inflammation-related cancer risk factors, we will perform whole genome sequencing and mutational signature analysis of a large cohort of colorectal tumors from patients with detailed, longitudinally collected lifestyle data (e.g., smoking, caloric intake, red meat intake, exercise level, etc.) collected by the Molecular Epidemiology of Colorectal Cancer study. We will also evaluate whether accumulation of ROS-generated mutations is biased toward CTCF binding loci and whether chromosomal architecture is modified by exposure to carcinogens or cancer- associated processes, thereby mediating unique “epigenomic signatures”. These aims will also provide data that can be used in the development of two novel computational tools for the analysis of cancer driver mutational signatures and epigenomic signatures of carcinogen exposure. Finally, we will test the molecular and clinical benefit of intermittent fasting during daily radiation therapy based on the hypothesis that lifestyle factors could modulate susceptibility to ROS mutagenesis. Patient- reported quality of life and clinician-reported adverse events, as well as molecular assay for tissue-specific levels of ROS-associated DNA damage, will allow us to assess whether intermittent fasting can reduce normal tissue toxicity. Successful completion of the proposed research will provide a comprehensive examination of the epidemiology and mechanism of ROS-mediated DNA damage in human cancers and demonstrate the safety and potential efficacy of intermittent fasting as a clinically translatable and easily adaptable approach to reducing both acute and chronic side effects associated with radiotherapy.

抽象的癌症是发达国家第二大最常见的死亡原因，事件正在上升发展中国家。估计有70％的癌症归因于“可修改”风险因素，包括肥胖，慢性炎症性疾病和饮食不良，所有这些疾病都与氧化增加有关压力。这些本身不是“致癌”，但被认为是“癌症促进者”，增加患癌症的可能性。随着整个基因组测序和发展的进步用于检查癌症基因组的计算技术，我们现在可以使用体细胞的数学分析突变特征（称为突变特征）以识别给定肿瘤的潜在原因（例如，吸烟与紫外线的光）。但是，尚不清楚，是否有一个突变签名是一种生物标志物累积寿命暴露于活性氧（ROS）介导的DNA损伤，如果该损伤相关与癌症相关的生活方式因素。在这里，我们将利用尖端的多摩尼克分析和分子生物学和计算工具，以更好地理解氧化应激的贡献/机制癌症促进者。检查ROS突变特征水平和炎症相关癌症风险的相关性因素，我们将对大量队列进行整个基因组测序和突变签名分析来自具有详细，纵向收集的生活方式数据的患者的结直肠肿瘤（例如吸烟，热量摄入量，红肉摄入量，运动水平等）由大肠癌的分子流行病学收集学习。我们还将评估ROS生成的突变的积累是否偏向CTCF 结合基因座以及是否通过暴露于致癌物或癌症 - 相关过程，从而介导了独特的“表观基因组签名”。这些目标也将提供数据可以用于开发两个新型计算工具，以分析癌症驱动器致癌物暴露的突变特征和表观基因组特征。最后，我们将测试每日放射治疗期间间歇性禁食的分子和临床益处基于以下假设：生活方式因素可以调节对ROS诱变的易感性。病人- 报告的生活质量和临床报告的不良事件以及组织特异性的分子测定与ROS相关的DNA损伤水平，将使我们能够评估间歇性禁食是否可以降低正常组织毒性。成功完成拟议的研究将提供对 ROS介导的DNA损伤在人类癌症中的流行病学和机制，并证明了间歇性禁食作为一种临床翻译且易于适应的方法的安全性和潜在有效性减少与放射疗法相关的急性和慢性副作用。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Moving the Needle Forward in Genomically-Guided Precision Radiation Treatment.

推动基因组引导精准放射治疗的发展。

DOI：
10.3390/cancers15225314
发表时间：
2023-11-07
期刊：
CANCERS
影响因子：
5.2
作者：
Tam, Andrew;Mercier, Benjamin D.;Thomas, Reeny M.;Tizpa, Eemon;Wong, Irene G.;Shi, Juncong;Garg, Rishabh;Hampel, Heather;Gray, Stacy W.;Williams, Terence;Bazan, Jose G.;Li, Yun R.
通讯作者：
Li, Yun R.