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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致癌应激的理解存在根本性差距。肿瘤发生过程中产生的内在 DNA 损伤，同时积累的突变会加剧癌症。不幸的是，在致癌过程中获得的 DNA 损伤耐受性和突变性也允许癌细胞抵抗治疗。填补目前我们在 DNA 损伤耐受性方面的知识空白将使我们能够利用内在的和治疗引起的 DNA 损伤来杀死癌细胞。我们的长期目标是解决癌细胞如何承受致癌压力和 DNA 损伤的问题。我们最近发现癌症细胞通常依赖于两个主要基因组维持途径的异常激活（Trans-Lesion 合成或 TLS，以及同源重组或 HR）以实现 DNA 损伤耐受。这种依赖 “病理激活”的 DNA 修复是癌细胞的一种新的分子脆弱性，并提供了机会用于高度选择性的靶向治疗。这里的目标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性 DNA 修复活动维持癌细胞生长并赋予治疗抵抗力。基本原理是定义病理机制激活的DNA修复将揭示针对癌细胞特定弱点的治疗策略。我们将使用以下具体目标 (SA) 检验我们的中心假设并实现我们的目标：SA1 阐明 MAGE-A4 激活 RAD18 的结构基础。 SA2 定义病理学的贡献- 激活跨损伤合成（TLS）对致癌应激耐受和体内致癌作用。 SA3 定义同源重组 (HR) 通过病理激活的新机制 HORMAD1 在癌症中的作用。 SA1将利用生物物理方法和新的肽探针来阐明其机制 MAGE-A4 通过它与 RAD18 相互作用。在缺乏 Rad18（TLS 顶端介质）的 SA2 突变小鼠中或过表达 MAGE-A4（TLS 的癌症特异性激活剂）的小鼠将用于确定 TLS 如何影响肿瘤发生和体内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/睾丸抗原 HORMAD1（在癌细胞）发出 DSB 修复激活、致癌应激耐受性和放射抗性的信号。我们建议针对致癌应激耐受性和突变性如何产生的重要问题提供创新的解决方案，促进癌变，并导致治疗耐药。拟议的工作很重要，因为我们将提供与环境暴露、诱变相关的基因组维护的新范例，人类肿瘤发生和癌症治疗。这项工作将带来新的治疗策略 DNA 损伤耐受性，特别是在癌细胞中，从而增强现有疗法的功效和选择性抗癌剂。