权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Pathological Reprogramming of DNA Damage Signaling in Neoplastic Cells

肿瘤细胞中 DNA 损伤信号的病理重编程

基本信息

批准号：
10301006
负责人：
Kenneth Hugh Pearce
金额：
$ 46.33万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10301006
关键词：
Antineoplastic Agents Apical Bacteriophages Binding Biochemical Biological Markers Cancer Cell Growth Carcinogenesis Mechanism Cause of Death Cell Culture Techniques Cell Survival Cells Cellular Assay Chemoresistance Complex Crystallization DNA Damage DNA Double Strand Break DNA Repair DNA biosynthesis DNA lesion Double Strand Break Repair Early identification Engineering Environmental Exposure Environmental Risk Factor Genes Genetic Genome Genome Stability Genomic Instability Genomics Genotoxic Stress Germ Cells Goals Human Individual Knowledge Lead Lesion Libraries Maintenance Malignant Neoplasms Mediator of activation protein Mission Modeling Molecular Mus Mutagenesis Mutant Strains Mice Mutation Oncogenes Oncogenic Outcome Pathologic Pathway interactions Peptide Library Peptides Permeability Phenotype Problem Solving Proteins Public Health Research Resistance Signal Transduction Source Stress Structure Testing Therapeutic Therapeutic Agents Tissues Toxic effect Trans-Activators Transgenic Mice United States National Institutes of Health Work biophysical techniques cancer cell cancer testis antigen cancer therapy carcinogenesis defined contribution druggable target environmental agent experience experimental study genotoxicity homologous recombination improved in vivo inhibitor innovation neoplastic cell new therapeutic target novel novel therapeutic intervention overexpression pressure prevent radiation resistance recruit replication stress response screening side effect stress tolerance targeted treatment therapy resistant tumor tumor molecular fingerprint tumorigenesis tumorigenic

项目摘要

SUMMARY There are fundamental gaps in our understanding of how neoplastic cells tolerate the oncogenic stress and intrinsic DNA damage that arises during tumorigenesis, while simultaneously accumulating mutations that fuel cancer. Unfortunately, the DNA damage tolerance and mutability acquired during carcinogenesis also allow cancer cells to resist therapy. Filling the current gaps in our knowledge of DNA damage tolerance will allow us to harness intrinsic and therapy-induced DNA damage to kill cancer cells. Our long-term goal is to solve the problem of how cancer cells endure oncogenic stress and DNA damage. We recently discovered that cancer cells commonly depend on aberrant activation of two major genome maintenance pathways (Trans-Lesion Synthesis or TLS, and Homologous Recombination or HR) for DNA damage tolerance. This reliance on 'pathologically-activated' DNA repair is a new molecular vulnerability of cancer cells and provides opportunities for highly selective targeted therapies. The objective here is to define signaling mechanisms by which cancer cells activate TLS and HR. Our central hypothesis is that pathological DNA repair activity sustains cancer cell growth and confers resistance to therapy. The rationale is that defining the mechanisms of pathologically- activated DNA repair will reveal therapeutic strategies that target specific vulnerabilities of cancer cells. We will test our central hypothesis and attain our objectives using the following Specific Aims (SAs): SA1 Elucidate structural basis for RAD18 activation by MAGE-A4. SA2 Define contribution of pathologically- activated Trans-Lesion Synthesis (TLS) to oncogenic stress tolerance and carcinogenesis in vivo. SA3 Define novel mechanism by which Homologous Recombination (HR) is pathologically activated via HORMAD1 in cancer. SA1 will use biophysical methods and new peptide probes to elucidate the mechanism by which MAGE-A4 interacts with RAD18. In SA2 mutant mice lacking Rad18 (the apical mediator of TLS) or mice overexpressing MAGE-A4 (a cancer-specific activator of TLS) will be used to determine how TLS impacts tumorigenesis and the genomic landscape of oncogene-driven cancers in vivo. For SA3 we will use cell culture models to determine how the cancer/testes antigen HORMAD1 (which is aberrantly over-expressed in cancer cells) signals activation of DSB repair, oncogenic stress tolerance and radioresistance. We propose innovative new solutions to the important problems of how oncogenic stress tolerance and mutability arise, drive carcinogenesis, and lead to therapy resistance. The proposed work is significant because we will provide new paradigms for genome maintenance that are relevant to environmental exposures, mutagenesis, tumorigenesis and cancer therapy in humans. This work will lead to novel therapeutic strategies that target DNA damage tolerance specifically in cancer cells, thereby enhancing the efficacy and selectivity of existing anti-cancer agents.

总结