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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.

项目摘要/摘要胶质母细胞瘤(GBM)是一种几乎没有临床选择的致命疾病。尽管外科手术取得了一定的进步手术、放疗和化疗，确诊后的中位生存期仅为14个月左右。在复发时，很少有存在有效的治疗选择。贝伐单抗，一种人源化的抑制血管内皮生长因子-A的单抗，收到了 2009年5月加快了FDA对用于复发性GBM的批准，并迅速成为复发性GBM的标准护理在美国的GBM。几乎所有的患者在治疗过程中都会接受贝伐单抗治疗。因为贝伐单抗在GBM的管理中发挥着如此重要的作用，开发成像生物标记物来提高风险分层和预测患者的利益是非常理想的。这样的生物标记物将在临床上用于识别将受益于贝伐单抗并对下一阶段的队列浓缩有科学意义的患者针对高危患者的联合疗法或探索性研究，其中常规疗法如贝伐单抗都有可能失败。广泛的初步数据(在400名患者中进行的7项试验)表明，弥散磁共振特征是一种强烈的、独立的复发肾小球基底膜患者抗血管内皮生长因子治疗效果的预测指标，如果患者在对比剂增强的肿瘤中表现为高表观扩散系数(ADC)。数据还表明，这些扩散 MR信号可能是由于核心蛋白(DCN)的表达升高所致，核心蛋白是一种具有多种功能的糖蛋白。我们假设生存优势和成像特征来自DCN的多方面功能，包括抗血管生成特性和细胞外基质的软化，我们理论上会导致增加抗血管内皮生长因子治疗的有效性和ADC的增加。目前的研究将探索DCN表达、弥散磁共振成像和抗血管内皮生长因子抗体之间的因果和机制联系治疗效果。首先，目标1将涉及对弥散磁共振表型和图像引导活检检测DCN蛋白在人GBM中的表达免疫组织化学和原位杂交法检测基因表达。弥散磁共振成像与弥散张量成像的关系表达，以及使用完整外显子组分析的相应的基因类型，使用批量RNA测序的遗传亚型，使用单细胞RNA测序的细胞状态和循环DCN的血浆水平也将被执行。同时，Aim 2将建立DCN表达、弥散磁共振测量、和抗血管内皮生长因子治疗通过复合钙，基因修饰的患者来源的原位异种移植(Pdx)。临床前试验。为了实现这一点，一系列患者来源的细胞系将被编辑为沉默过表达的DCN PDX模型使用四环素控制的基因表达系统。DCN的表达在改变中的直接作用磁共振弥散成像测量和通过开启或关闭DCN表达来提高抗血管内皮生长因子治疗后的生存率使用多西环素将被确定。