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

• 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
• 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

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.

摘要

项目成果

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.