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.

项目概要/摘要胶质母细胞瘤（GBM）是一种致命的疾病，临床选择很少。尽管外科手术取得了一定进展手术、放疗和化疗，诊断后的中位生存期仅为 14 个月左右。复发后，很少存在有效的治疗选择。贝伐单抗（Bevacizumab）是一种抑制 VEGF-A 的人源化单克隆抗体， 2009 年 5 月，FDA 加速批准用于治疗复发性 GBM，并迅速成为复发性 GBM 的治疗标准 GBM 在美国。几乎所有患者在治疗过程中的某个阶段都会接受贝伐珠单抗治疗。因为贝伐珠单抗在 GBM 的管理、成像生物标志物的开发以降低风险方面发挥着如此重要的作用分层并预测患者获益是非常必要的。这种生物标志物在临床上可用于识别将从贝伐珠单抗中受益的患者以及在科学上对下一阶段的队列富集有用的患者针对高危患者的联合疗法或探索性研究，其中传统疗法如贝伐珠单抗很可能会失败。广泛的初步数据（超过 7 项试验，超过 400 名患者）表明扩散 MRI 特征是一个强有力的、独立的复发性 GBM 中抗 VEGF 治疗效果的预测因子，如果患者能够表现出显着的生存获益在对比增强肿瘤内呈现出高表观扩散系数（ADC）。数据还表明这些扩散 MR 特征可能是由于核心蛋白聚糖 (DCN) 表达升高所致，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源自 DCN 的多方面功能，其中包括抗血管生成特性和细胞外基质软化，我们理论上会导致增加抗 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 之间的因果关系和机制联系治疗效果。首先，目标 1 将深入探索扩散 MR 表型与使用图像引导活检检测人类 GBM 中的 DCN 表达并使用使用原位杂交进行免疫组织化学和基因表达。弥散MRI、DCN之间的关系使用全外显子组分析确定表达和相应的基因型，使用批量 RNA 测序确定遗传亚型，还将使用单细胞 RNA 测序来检测细胞状态，以及循环 DCN 的血浆水平。同时，目标 2 将建立 DCN 表达、扩散 MRI 测量、以及通过 ca 复合物、转基因患者来源的原位异种移植物 (PDX) 进行 GBM 抗 VEGF 治疗临床前试验。为了实现这一目标，将对一系列患者来源的细胞系进行编辑，以沉默体内过表达的 DCN 使用四环素控制的基因表达系统进行 PDX 模型。 DCN表达在变化中的直接作用扩散 MRI 测量并通过打开或关闭 DCN 表达来提高抗 VEGF 治疗后的生存率使用强力霉素即可确定。