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Rewiring of epigenetic DNA damage response pathways in HPV-induced cancer

HPV 诱导的癌症中表观遗传 DNA 损伤反应途径的重新布线

基本信息

批准号：
10474489
负责人：
Michael Goldstein
金额：
$ 21.92万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2022-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10474489
关键词：
Acetylation Affect Aneuploidy Basic Science CRISPR screen Cancer Biology Cancer Patient Cell physiology Cells Centromere Chemicals Chromatids Chromatin Chromatin Remodeling Factor Chromosome abnormality Clinical DNA Damage DNA Repair DNA biosynthesis DNA replication fork Data Defect Dependence Development Doctor of Philosophy EP300 gene Epigenetic Process Exhibits Genetic Transcription Goals Head and Neck Cancer Histone Acetylation Histones Human Papilloma Virus-Related Malignant Neoplasm Human Papillomavirus Incidence Infection Investigation Laboratory Research Laboratory Study Link Locally Advanced Malignant Neoplasm Malignant Neoplasms Malignant neoplasm of anus Malignant neoplasm of cervix uteri Mentorship Microtubules Mitosis Mitotic Mitotic spindle Molecular Nonhomologous DNA End Joining Outcome Pathway interactions Patients Play Predisposition Protein Acetylation Proteins Radiation Radiation Induced DNA Damage Radiation Oncology Radiation therapy Recurrence Relapse Research Research Personnel Resolution Role Salvage Therapy Signal Pathway Signal Transduction Site Survival Rate Techniques Testing Tissues Training Work advanced disease cancer cell cancer radiation therapy cancer therapy career chromatin modification coping endonuclease epigenomics gene product histone methylation histone modification homologous recombination improved in vivo insight irradiation mouse model novel novel strategies p53-binding protein 1 protein complex radiation response recruit response segregation targeted treatment treatment strategy tumor tumor specificity ubiquitin-protein ligase

项目摘要

Project summary/abstract Infection with human papilloma virus (HPV) causes endemic occurrence of cervical, head and neck and anal cancers. Radiotherapy is the cornerstone treatment for these tumors. However, clinical outcomes in patients with locally advanced disease remain poor due to high recurrence rates. Thus, there is a critical need to improve the efficacy of radiation in these tumors. Epigenetic signaling pathways play a crucial role in DNA damage response providing suitable clinical targets for improving the efficacy of radiotherapy. We demonstrate that expression of the HPV proteins E6 and E7 alters epigenetic signaling in cancer cells. We hypothesize that these epigenomic alterations cause tumor dependence on alternative epigenetic pathways to cope with DNA damage. Using a CRISPR/Cas9 screen we discovered that HPV-positive cancer cells selectively depend on the chromatin modifier NSL1 and the E3 ubiquitin ligase RNF168 to survive radiation. The goal of this proposal is to determine the mechanisms of DNA damage response (DDR) regulated by these pathways in the setting of HPV-induced epigenetic changes. Our work will establish a novel concept of tumor-targeted therapy by harnessing HPV- induced epigenomic alterations to allow specific targeting of cancer cells while sparing healthy tissues. The work proposed here will be conducted under the mentorship of Dr. Dennis Hallahan, a leader clinical and experimental radiation oncology. The candidate is an MD/PhD with training in clinical radiation oncology who seeks further training in basic research. His long-term goal is to establish an independent research laboratory studying the role of epigenetics in DDR. It is anticipated that the project will result in impactful contributions to the fields of DDR and Radiation Oncology and prepare the candidate for a career as an independent investigator.

项目概要/摘要人乳头瘤病毒（HPV）感染可引起宫颈、头颈部和肛门的地方性发病癌的放射治疗是这些肿瘤的基础治疗。然而，患者的临床结局由于复发率高，局部晚期疾病仍然很差。因此，迫切需要改进放射治疗在这些肿瘤中的疗效。表观遗传信号通路在DNA损伤反应中起着重要作用为提高放射治疗的疗效提供了合适的临床靶点。我们证明， HPV蛋白E6和E7改变癌细胞中的表观遗传信号。我们假设这些表观基因组改变导致肿瘤依赖于替代表观遗传途径来科普DNA损伤。使用 CRISPR/Cas9筛选我们发现HPV阳性癌细胞选择性依赖于染色质修饰剂 NSL 1和E3泛素连接酶RNF 168在辐射中存活。本提案的目的是确定这些通路在HPV诱导的DNA损伤反应（DDR）中的调节机制，表观遗传变化我们的工作将通过利用HPV建立肿瘤靶向治疗的新概念- 诱导表观基因组改变，以允许特异性靶向癌细胞，同时保留健康组织。工作这里提出的将在丹尼斯·哈拉汉博士的指导下进行，他是临床和实验的领导者。放射肿瘤学候选人是一名医学博士/博士，接受过临床放射肿瘤学培训，基础研究培训。他的长期目标是建立一个独立的研究实验室，表观遗传学在DDR中的作用。预计该项目将对以下领域做出有影响力的贡献： DDR和放射肿瘤学，并准备候选人的职业生涯作为一个独立的调查员。