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Extrachromosomal DNA as a Targetable Mechanism in Glioblastoma

染色体外 DNA 作为胶质母细胞瘤的靶向机制

基本信息

批准号：
10063975
负责人：
Roel GW Verhaak
金额：
$ 51.81万
依托单位：
JACKSON LABORATORY
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：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10063975
关键词：
Affect Amplifiers Animal Model Behavior Binding Biological Models Biology CRISPR/Cas technology Cancer Cell Growth Cell model Cells Characteristics Chromatin Chromatin Interaction Analysis by Paired-End Tag Sequencing Chromosomal Duplication Clustered Regularly Interspaced Short Palindromic Repeats Cytopathology DNA DNA Sequence Alteration DNA amplification DNA biosynthesis Data Data Set Deoxyribonucleotides Development Double Minutes Elements Enhancers Enzymes Esophageal carcinoma Evolution Frequencies Gene Amplification Genetic Transcription Genomics Glioblastoma Goals Growth Heterogeneity Hybrids In Vitro Knowledge Label Laboratories Location Maintenance Malignant Neoplasms Mediating Methods Methotrexate Mitosis Modeling Molecular Monitor Oncogene Activation Oncogenes Oncogenic Outcome Patients Pharmacology Proteins RNA Polymerase II RRM1 gene RRM2 gene Regulation Reporting Research Resistance Ribonucleotide Reductase Ribonucleotide Reductase Subunit Role S Phase Solid Structure System Technology Testing Therapeutic Time Visualization software Work base cancer cell cancer genome cancer therapy cancer type cell behavior cell killing dosage endonuclease extrachromosomal DNA gemcitabine genetic element genomic locus hydroxyurea in vivo Model innovation insight interest neoplastic cell novel patient derived xenograft model real-time images sarcoma therapeutic target tool tripolyphosphate tumor tumor DNA tumor growth tumor heterogeneity tumorigenesis virtual

项目摘要

PROJECT SUMMARY/ABSTRACT The goal of this project is to determine the influence of extrachromosomal DNA (ecDNA) on tumor evolution and resistance and to validate a potential therapeutic strategy based on ecDNA inhibition. The existence of ecDNA was first recognized through pioneering cytopathology studies by Arthur Spriggs over five decades ago. We know that ecDNAs are largely a phenomenon of tumor cells, can be detected in nearly half of all solid cancers, and frequently express oncogenes, making them vehicles for amplification of oncogene expression and consequent tumorigenesis. Our studies in glioblastoma extend this knowledge, showing that ecDNAs are highly pervasive and significantly increase intra-tumoral genomic heterogeneity. Despite this knowledge, research into the mechanisms of ecDNA-driven tumorigenesis is largely non-existent. To advance ecDNA research to the next level of understanding, we must now define its origins, replication mechanisms, and strategies to target it for treatment. At this time, however, there are significant barriers to such studies, such as the absence of profiling technologies and molecular tools to accurately detect and characterize these oncogenic elements. The work proposed here will remove these barriers to progress. We hypothesize that ecDNAs drive tumorigenesis beyond their role as oncogene activators, and that mechanisms of ecDNA formation and replication could serve as potential therapeutic targets. To test our hypothesis, we will develop methods to visualize and trace ecDNA in live cells and use these tools to define the mechanisms of ecDNA localization and transfer within a tumor. We will functionally evaluate whether ecDNA mediated cis-regulation of non-ecDNA gene transcription can be modulated to change tumor cell behavior. Finally, we will explore whether pharmacological depletion of ecDNA affects tumor growth and maintenance in cellular and animal model systems. Our Specific Aims are to: 1) Develop CRISPR-based tracing tools for real-time imaging of ecDNA dynamics; 2) Discovery and functional interrogation of ecDNA mediated oncogene activation; and 3) Target ecDNA through inhibition of ribonucleotide reductase (RNR), the enzyme responsible for generating the deoxyribonucleotide triphosphates that are the building blocks of autosomal and extrachromosomal DNA. Impact: This project is based on the conceptual innovation that ecDNAs are cancer-specific and cancer- enabling genomic alterations. Despite the recognition of ecDNA decades ago, the function of these structures and how to effectively target their genesis, is virtually uncharted territory. In addition to developing new, broadly applicable, tools for ecDNA studies, the results of this work will provide novel insights into the characteristics, behavior and replicative mechanism of ecDNA, and will assess whether ecDNA is an unexploited cancer cell vulnerability that can be therapeutically exploited for patient benefit.

项目总结/文摘