Enlisting HPV integration events to illuminate drivers and target treatment in invasive cervical cancer

招募 HPV 整合事件来阐明浸润性宫颈癌的驱动因素和靶向治疗

• 批准号: 10666600
• 负责人: Janet S. Rader
• 金额: $ 38.91万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666600
• 关键词: Affect; Automobile Driving; CRISPR/Cas technology; Cancer cell line; Cell Proliferation; Cell Survival; Cells; Cessation of life; ChIP-seq; Chromatin Loop; Chromosomes; Cisplatin; Clinical; Clinical Data; Clonality; Clustered Regularly Interspaced Short Palindromic Repeats; Complementary DNA; Complex; Copy Number Polymorphism; DNA; DNA Methylation; DNA amplification; DNA sequencing; Data; Data Set; Disease; Disease Progression; Elements; Enhancers; Event; Frequencies; Gene Expression; Gene Modified; Genes; Genome; Genomics; Goals; HIV; Haplotypes; Histology; Human Papillomavirus; Immunofluorescence Immunologic; In Vitro; Invaded; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Mediating; Methylation; Minority Groups; Minority Women; Modification; Molecular; Multiomic Data; Neoplasm Metastasis; Nucleic Acid Regulatory Sequences; Oncogenes; Pathologic; Pathology; Pathway interactions; Patients; Positron-Emission Tomography; Recurrence; Research; Residual Neoplasm; Resistance development; Role; Sampling; Small Interfering RNA; Technology; Testing; The Cancer Genome Atlas; Tissues; Transcript; Transcriptional Regulation; Validation; Viral; Woman; Xenograft Model; cancer survival; cervical carcinogenesis; chemotherapy; clinical biomarkers; clinically relevant; cohort; cytotoxicity; design; epigenome; epigenomics; fitness; fluorodeoxyglucose positron emission tomography; gene network; genome sequencing; human papilloma virus oncogene; improved; in vivo; individual patient; insight; integration site; knock-down; knockout gene; low socioeconomic status; migration; multiple omics; nanopore; new technology; novel; novel strategies; novel therapeutics; protein expression; response; screening; targeted treatment; therapeutic target; transcriptome; transcriptome sequencing; treatment and outcome; tumor; tumor microenvironment; whole genome; years of life lost

PROJECT SUMMARY Invasive cervical cancer (ICC) kills nearly 311,000 women each year worldwide with an estimated 50% increase in deaths by 2040. In the U.S., ICC ranks third for average years of life lost and disproportionately affects minority groups and women of low socioeconomic status. Women with advanced or recurrent ICC soon develop resistance to current chemotherapy options, and about 90% die within 2 years. Our intent is to define clinically relevant and targetable ICC genes and pathways to improve patients’ treatments and outcomes. Our central hypothesis is that HPV integration events—and the changes they exert on the host genome and epigenome—confer a selective advantage to disease progression and provide opportunities to pinpoint genes and pathways relevant to treating ICC. Using The Cancer Genome Atlas (TCGA) ICC cohort (CESC), we developed a pipeline to identify integration detected genes (IDGs) altered by HPV integration in some ICCs and by genomic and/or epigenomic modifications in other ICCs. Elements of our pipeline focus on proximity to the integration site, clonal representation of the integration event, patient- and disease-specific gene expression, association with ICC survival, and frequency of alteration in ICC. For this proposal, we will expand our discovery pipeline to a newly completed multi-omics ICC cohort, the HTMCP (HIV+ Tumor Molecular Characterization Project), incorporating new technology and testing the functional contribution of IDGs to ICC and chemoresponse. This in-depth characterization of a plethora of IDGs will help us identify novel targets/pathways which is a critical step towards better therapy for women with ICC. To this end, we will pursue the following Specific Aims: Identify and filter IDGs from HPV integration sites in HTMCP samples using our established pipeline, long-read DNA and cDNA sequencing, and other genomic studies (Aim 1), determine the functional contribution of IDGs to ICC and their therapeutic targeting potential using siRNA-mediated KD and/or CRISPR-based gene editing in cervical cancer cell lines and orthotopic xenograft models, (Aim 2), and determine the clinical relevance and biomarker potential of IDGs (Aim 3).

项目摘要 侵袭性宫颈癌（ICC）每年在全球范围内杀死近311，000名妇女，估计50% 到2040年死亡人数增加。在美国，ICC在平均寿命损失方面排名第三， 对少数群体和社会经济地位低的妇女的影响尤为严重。妇女 晚期或复发性ICC很快就会对目前的化疗方案产生耐药性，约90%的患者会对化疗方案产生耐药性。 两年内死亡。我们的目的是确定临床相关和靶向ICC基因和途径， 改善患者的治疗和结果。我们的中心假设是，HPV整合事件， 它们对宿主基因组和表观基因组产生的改变赋予疾病选择优势 进展，并提供机会，以查明相关的基因和途径，以治疗ICC。使用 癌症基因组图谱（TCGA）ICC队列（CESC），我们开发了一个管道，以确定整合 检测到的基因（IDG）在一些ICC中被HPV整合改变，以及在一些ICC中被基因组和/或表观基因组整合改变。 其他ICC的修改。我们的管道元素集中在接近整合位点，克隆 整合事件的代表性，患者和疾病特异性基因表达， ICC的存活率和ICC改变的频率。对于这项提案，我们将扩大我们的发现管道 到一个新完成的多组学ICC队列，HTMCP（HIV+肿瘤分子表征） 项目），采用新技术并测试国际发展集团对电算中心的职能贡献， 化学反应这种对过多IDG的深入描述将有助于我们识别新的 目标/途径，这是改善ICC女性治疗的关键一步。为此我们将 追求以下具体目标：从HTMCP中的HPV整合位点识别和过滤IDG 样本使用我们建立的管道，长读段DNA和cDNA测序，以及其他基因组 研究（目的1），确定IDG对ICC的功能贡献及其治疗靶向 在宫颈癌细胞系中使用siRNA介导的KD和/或基于CRISPR的基因编辑的潜力， 原位异种移植模型，（目的2），并确定临床相关性和生物标志物的潜力， 国际发展集团（目标3）。