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.

概括我们对肿瘤细胞如何耐受致癌应激和肿瘤发生期间产生的固有DNA损伤，同时积累了燃料的突变癌症。不幸的是，在致癌过程中获得的DNA损伤耐受性和可突变性也允许癌细胞抵抗治疗。填补我们对DNA损伤耐受性的了解中的当前空白将使我们利用固有和治疗诱导的DNA损伤以杀死癌细胞。我们的长期目标是解决癌细胞如何忍受致癌应激和DNA损伤的问题。我们最近发现癌症细胞通常取决于两个主要基因组维持途径的异常激活（跨性质用于DNA损伤耐受性的合成或TLS以及同源重组或HR）。这种依赖 “病理激活”的DNA修复是癌细胞的新分子脆弱性，并提供机会用于高度选择性的靶向疗法。这里的目的是定义癌症的信号传导机制细胞激活TLS和HR。我们的中心假设是病理DNA修复活性维持癌细胞生长并赋予对治疗的抵抗力。理由是定义病理学机制活化的DNA修复将揭示针对癌细胞特定脆弱性的治疗策略。我们将测试我们的中心假设，并使用以下特定目的（SAS）实现我们的目标：SA1 MAGE-A4激活RAD18的结构基础。 SA2定义了病理学的贡献活体内的致癌胁迫耐受性和致癌作用的激活的转换合成（TLS）。 SA3定义了新机制，通过该机制，通过该机制通过病理（HR）通过病理激活癌症中的Hormad1。 SA1将使用生物物理方法和新的肽探针来阐明机制 Mage-A4与Rad18相互作用。在缺乏RAD18（TLS的顶端介体）的SA2突变小鼠中过表达MAGE-A4的小鼠（TLS的癌症特异性激活剂）将用于确定TLS如何影响肿瘤发生和体内致癌基因驱动的癌症的基因组景观。对于SA3，我们将使用单元格培养模型以确定癌症/睾丸如何使用抗原hormad1（在癌细胞）信号激活DSB修复，致癌胁迫耐受性和放射线抗性。我们建议创新的新解决方案对于如何出现致癌胁迫的耐受性和可突变性的重要问题，驱动致癌，并导致抗治疗性。拟议的工作很重要，因为我们将提供基因组维持的新范例与环境暴露，诱变，人类的肿瘤发生和癌症治疗。这项工作将导致针对的新型治疗策略 DNA损伤耐受性在癌细胞中，从而提高了现有的功效和选择性抗癌代理商。