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:
  • 金额:
    $ 62.3万
  • 依托单位:
  • 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

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

项目成果

期刊论文数量(0)
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TIMOTHY CLOUGHESY其他文献

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{{ truncateString('TIMOTHY CLOUGHESY', 18)}}的其他基金

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
  • 批准号:
    10590620
  • 财政年份:
    2022
  • 资助金额:
    $ 62.3万
  • 项目类别:
Career Enhancement Program
职业提升计划
  • 批准号:
    10225555
  • 财政年份:
    2017
  • 资助金额:
    $ 62.3万
  • 项目类别:
Career Enhancement Program
职业提升计划
  • 批准号:
    9983052
  • 财政年份:
    2017
  • 资助金额:
    $ 62.3万
  • 项目类别:
UCLA IRB (PENDING) "A PHASE I/II STUDIES OF BAY 43-9006 (SORAFENIB) IN COMBIN
加州大学洛杉矶分校 IRB(待定)“Bay 43-9006(索拉非尼)组合的 I/II 期研究
  • 批准号:
    7951564
  • 财政年份:
    2009
  • 资助金额:
    $ 62.3万
  • 项目类别:
PHASE I/II STUDY OF OSI-774 (ERLOTINIB) AND CCI-779 (TEMSIROLIMUS) IN PATIENT
OSI-774(埃洛替尼)和 CCI-779(替西罗莫司)在患者中的 I/II 期研究
  • 批准号:
    8167082
  • 财政年份:
    2009
  • 资助金额:
    $ 62.3万
  • 项目类别:
UCLA IRB # 06-04-104 "A PHASE I/II, DUAL-CENTER, OPEN-LABEL TRIAL OF THE SAFE
加州大学洛杉矶分校IRB
  • 批准号:
    7951565
  • 财政年份:
    2009
  • 资助金额:
    $ 62.3万
  • 项目类别:
UCLA IRB # 06-04-016 "PHASE II TRIAL OF BEVACIZUMAB IN COMBINATION WITH TEMOZ
加州大学洛杉矶分校IRB
  • 批准号:
    8167096
  • 财政年份:
    2009
  • 资助金额:
    $ 62.3万
  • 项目类别:
UCLA IRB #05-12-061 "A PHASE I STUDY OF VORINOSTAT (SUBEROYLANILIDE HYDROXAMI
加州大学洛杉矶分校IRB
  • 批准号:
    7951558
  • 财政年份:
    2009
  • 资助金额:
    $ 62.3万
  • 项目类别:
UCLA IRB 08-09-042: PHASE I TRIAL OF AFLIBERCEPT (VEGF TRAP) WITH RADIATION THE
加州大学洛杉矶分校 IRB 08-09-042:AFLIBERCEPT(VEGF TRAP)的 I 期试验与辐射
  • 批准号:
    8167134
  • 财政年份:
    2009
  • 资助金额:
    $ 62.3万
  • 项目类别:
UCLA IRB # 06-04-016 "PHASE II TRIAL OF BEVACIZUMAB IN COMBINATION WITH TEMOZ
加州大学洛杉矶分校IRB
  • 批准号:
    7951566
  • 财政年份:
    2009
  • 资助金额:
    $ 62.3万
  • 项目类别:

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