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Tissue Factor as a Key Determinant of IDH1 Mutant versus IDH1 Wild-type Glioma Thrombosis and Malignancy

组织因子是 IDH1 突变型与 IDH1 野生型胶质瘤血栓形成和恶性肿瘤的关键决定因素

基本信息

批准号：
9980502
负责人：
Craig Michael Horbinski
金额：
$ 34.56万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9980502
关键词：
Adult Affect Apoptosis Binding Biological Assay Biological Markers Blood Blood Circulation Blood Coagulation Factor Blood coagulation CRISPR/Cas technology Cancer Patient Cell Culture Techniques Cells Cerebral hemisphere hemorrhage Cessation of life Characteristics Clinical Clinical Management Coagulation Process Code Complementary DNA Complex Complication DNA Data Decitabine Diagnostic F3 gene Factor VIIa Factor X Gene Silencing Genes Genetic Transcription Glioma Gliomagenesis Goals Growth Hypermethylation Iatrogenesis In Vitro Isocitrate Dehydrogenase Link Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Mediating Messenger RNA Methylation Molecular Mus Mutate Mutation Nature Outcome PAR-2 Receptor Pathway interactions Patient Care Patients Pharmacology Phenotype Primary Brain Neoplasms Production Prophylactic treatment Prospective cohort Proteins Publishing Regulation Reporter Reporting Research Risk Role Series Signal Transduction Site Testing Therapeutic Thromboplastin Thrombosis Thrombus Tissues Tumor Biology United States Untranslated RNA Venous Work Xenograft procedure alpha ketoglutarate base cancer cell improved in vivo inhibitor/antagonist mouse model mutant neoplastic cell new therapeutic target novel outcome forecast predictive modeling prevent promoter prospective receptor thrombogenesis tumor tumor behavior

项目摘要

PROJECT SUMMARY/ABSTRACT Infiltrative glioma is the most common type of primary brain tumor in adults, causing over 17,000 deaths in the United States every year. Approximately 20-30% of infiltrative gliomas contain mutations in isocitrate dehydrogenase 1 (IDH1mut). IDH1mut causes global DNA hypermethylation, which contributes to gliomagenesis. Yet, IDH1mut gliomas are significantly less aggressive than gliomas lacking this mutation. It has remained unclear how DNA hypermethylation leads to this unique phenotype. Gliomas often produce blood clots (thrombi) within the tumor and throughout the bloodstream. These thrombi have long been known to be predictors of poor outcome. We recently reported that IDH1mut gliomas produce far fewer thrombi; our data strongly indicate that methylation-induced suppression of F3, the gene encoding Tissue Factor (TF), is the reason why. TF is a powerful procoagulant that, when produced and released by cancers, causes venous thromboemboli (VTE). This debilitating phenomenon occurs in ~25% of glioma patients, but never when IDH1mut is present. In addition to triggering thrombosis, TF binds and activates protease-activated receptor 2 (PAR2), a transmembrane receptor expressed by cancer cells that signals through multiple intracellular pathways to promote tumor malignancy. Our data show that: (i) among all genes that directly participate in blood clotting, F3 mRNA levels have the strongest inverse relationship with IDH1mut; (ii) F3 methylation is significantly higher in IDH1mut gliomas than IDH1wt gliomas; (iii) TF protein levels are consistently lower in IDH1mut gliomas than IDH1wt gliomas; (iv) circulating TF is lower in patients with IDH1mut gliomas than IDH1wt gliomas; (v) high circulating TF correlates with increased VTE risk; (vi) patient-derived glioma cells with endogenous IDH1mut produce smaller and fewer venous thrombi than IDH1wt gliomas in xenograft mouse models; (vii) suppression of TF in IDH1wt gliomas greatly reduces their in vitro and in vivo malignancy; (viii) patients whose gliomas express low TF have more than double the median survival of patients whose gliomas express high TF, independent of IDH1mut. Thus, we hypothesize that methylation- induced suppression of TF is a critical determinant of the less thrombogenic, and less malignant, IDH1mut phenotype. In Aim 1, we will conclusively establish that F3 hypermethylation is the mechanism by which IDH1mut suppresses TF expression. In Aim 2, we will modulate the expression of TF in a series of patient-derived IDH1wt and IDH1mut glioma cells, observing the effects on tumor-induced thrombosis and malignancy in cell cultures and in engrafted mice. In Aim 3, we will use molecular and pharmacologic approaches to investigate the therapeutic potential of blocking TF-PAR2 signaling in gliomas. Further, we will prospectively evaluate the utility of determining circulating TF levels, along with other clinical, blood-based, and tissue-based biomarkers, to create the first predictive model of VTE risk in glioma patients. In total, this research will greatly advance our understanding of IDH1mut tumor biology, and it will inform regarding novel treatment and diagnostic strategies for improving glioma patient care.

项目总结/文摘