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Role of decorin and diffusion MRI in anti-VEGF efficacy for recurrent glioblastoma

核心蛋白聚糖和扩散 MRI 在复发性胶质母细胞瘤抗 VEGF 疗效中的作用

基本信息

批准号：
10419491
负责人：
TIMOTHY CLOUGHESY
金额：
$ 62.3万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
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：
2022-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10419491
关键词：
Address Angiogenic Factor Biological Markers Biopsy Blood Cell Line Characteristics Chemotherapy and/or radiation Clinical Clinical Trials Combined Modality Therapy Complex Controlled Clinical Trials DNA Data Development Diagnosis Diffuse Diffusion Diffusion Magnetic Resonance Imaging Disease Doxycycline Effectiveness Epidermal Growth Factor Receptor Exhibits Extracellular Matrix Gene Expression Genetic Genetic Transcription Genotype Glioblastoma Glycoproteins Human Image Image Guided Biopsy Immunohistochemistry In Situ Hybridization Link Magnetic Resonance Imaging Measurable Measurement Measures Mesenchymal Modeling Nature Operative Surgical Procedures PTEN gene Patients Phase Phenotype Placebos Plasma Play Pre-Clinical Model Prior Therapy Proteins Randomized Recurrence Reproducibility Role Series System Testing Tetracyclines Therapeutic Treatment Efficacy Tumor Tissue United States Vascular Endothelial Growth Factors Water Xenograft Model Xenograft procedure bevacizumab cancer imaging cohort comparative efficacy contrast enhanced conventional therapy cost decorin economic impact effective therapy exhaust exhaustion exome experience high risk humanized monoclonal antibodies imaging biomarker improved inhibiting antibody neoplastic cell novel overexpression patient derived xenograft model phase II trial preclinical trial predictive marker predictive tools protein expression response response biomarker risk stratification single-cell RNA sequencing standard of care theories transcriptome sequencing tumor

项目摘要

PROJECT SUMMARY/ABSTRACT Glioblastoma (GBM) is a uniformly fatal disease with very few clinical options. Despite modest advancements in surgical procedures, radiation and chemotherapy, median survival from diagnosis is only around 14 months. Upon recurrence, few effective treatment options exist. Bevacizumab, a humanized monoclonal antibody that inhibits VEGF-A, received accelerated FDA approval in May 2009 for use in recurrent GBM and quickly became the standard of care for recurrent GBM in the United States. Almost all patients receive bevacizumab at some point in their treatment. Because bevacizumab plays such an important role in the management of GBM, the development of imaging biomarkers to improve risk stratification and predict patient benefit is highly desired. Such a biomarker would be clinically useful for identifying patients that will benefit from bevacizumab as well as scientifically useful for cohort enrichment in the next phase of combination therapies or exploratory studies aimed at high-risk patients, where conventional therapies like bevacizumab are likely to fail. Extensive preliminary data (>7 trials in >400 patients) suggests diffusion MRI characteristics are a strong, independent predictor of anti-VEGF therapeutic efficacy in recurrent GBM, with patients exhibiting a significant survival benefit if they present with a high apparent diffusion coefficient (ADC) within contrast enhancing tumor. Data also suggests these diffusion MR signatures may result from an elevated expression of decorin (DCN), a glycoprotein with a variety of functions. We hypothesize that the survival advantage and imaging signatures arise from the multifaceted functions of DCN, which include anti-angiogenic characteristics and softening of the extracellular matrix, which we theorize would result in increased effectiveness of anti-VEGF therapies and an increase in ADC. The current study will explore the causal, mechanistic links between DCN expression, diffusion MRI, and anti-VEGF treatment efficacy. First, Aim 1 will involve a deep exploration into the association between diffusion MR phenotypes and DCN expression in human GBM using image-guided biopsies and examining DCN protein expression using immunohistochemistry and gene expression using in-situ hybridization. The relationship between diffusion MRI, DCN expression, and corresponding genotypes using whole exome analysis, genetic subtypes using bulk RNA sequencing, cellular states using single-cell RNA sequencing, and blood plasma levels of circulating DCN will also be performed. Concurrently, Aim 2 will establish the causal, mechanistic links between DCN expression, diffusion MRI measurements, and anti-VEGF treatment in GBM through ca complex, genetically modified patient-derived orthotopic xenograft (PDX) preclinical trial. To accomplish this, a series of patient-derived cell lines will be edited to silence of overexpress DCN within PDX models using a tetracycline-controlled gene expression system. The direct role of DCN expression in changing diffusion MRI measurements and increasing survival following anti-VEGF therapy by turning on or off DCN expression using doxycycline will be determined.

项目总结/文摘