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：
10590620
负责人：
TIMOTHY CLOUGHESY
金额：
$ 60.57万
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/10590620
关键词：
Acceleration Address Angiogenesis Inhibitors 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 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 Randomized Recurrence Reproducibility Role Series System Testing Tetracyclines Therapeutic Treatment Efficacy Tumor Tissue United States VEGFA gene Vegf inhibition Water Xenograft Model Xenograft procedure bevacizumab cancer imaging cohort comparative efficacy contrast enhanced conventional therapy cost decorin economic impact effective therapy exhaust exome experience high risk humanized monoclonal antibodies imaging biomarker improved neoplastic cell novel overexpression patient derived xenograft model phase II trial preclinical trial predictive marker predictive tools protein expression response response biomarker risk prediction 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）是一种统一致命疾病，几乎没有临床选择。尽管手术方面的进步不大程序，放射和化学疗法，诊断的中位生存期仅约14个月。复发，很少存在有效的治疗选择。贝伐单抗是一种抑制VEGF-A的人源化单克隆抗体，接受了 2009年5月加速FDA批准用于经常性GBM，并迅速成为经常性的护理标准在美国的GBM。几乎所有患者在治疗的某个时候都会接受贝伐单抗。因为贝伐单抗在GBM的管理中起着如此重要的作用，发展成像生物标志物以改善风险高度需要分层和预测患者益处。这样的生物标志物在临床上对于识别将从贝伐单抗中受益的患者以及科学在下一阶段的人群中有用的患者针对高风险患者的组合疗法或探索性研究，贝伐单抗等常规疗法可能失败。广泛的初步数据（> 400名患者的7个试验）表明，扩散MRI特征是一个强大的，独立的反复GBM中抗VEGF治疗功效的预测指标，如果患者表现出显着的生存益处在对比度增强肿瘤中具有高表观扩散系数（ADC）。数据还表明这些扩散 MR签名可能是由DecorIn（DCN）表达升高的，DCN（DCN）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，其中包括抗血管生成特征和细胞外基质的软化，我们将其理论化会导致增加抗VEGF疗法的有效性和ADC的增加。当前的研究将探讨DCN表达，扩散MRI和抗VEGF之间的因果关系，机械联系治疗功效。首先，AIM 1将涉及对扩散MR表型与使用图像引导的活检和使用DCN蛋白表达的DCN表达DCN在人类GBM中的表达使用原位杂交的免疫组织化学和基因表达。扩散MRI，DCN之间的关系表达和相应的基因型使用整个外显子组分析，使用大量RNA测序的遗传亚型，还将使用单细胞RNA测序和血浆循环DCN的血浆水平进行细胞态。同时，AIM 2将建立DCN表达，扩散MRI测量的因果，机械联系，通过CA复合物，基因改良的患者衍生的原始异种移植（PDX），在GBM中进行抗VEGF处理临床前试验。为此，将对一系列患者衍生的细胞系进行编辑，以使过表达DCN在内 PDX使用四环素控制的基因表达系统模型。 DCN表达在变化中的直接作用通过打开或关闭DCN表达，抗VEGF治疗后的扩散MRI测量和增加生存率将确定使用强力霉素。