Defining the Hypoxic Immunosuppressive Microenvironment as a Biomarker of Therapy Efficacy in Glioblastoma Using Iron Oxide Enhanced FMISO PET/MRI

摘要 该K 08提案描述了一个5年职业发展计划，目标是支持Ramon弗朗西斯科博士 巴拉哈斯的进步，以独立的早期阶段的医生，科学家的作用。巴拉哈斯博士已经完成了 在加州大学旧金山弗朗西斯科接受放射诊断学和神经放射学临床培训 目前是放射学系和高级成像研究中心的助理教授 在俄勒冈州健康与科学大学（OHSU）。Edward Neuwelt医学博士，药物输送和分子生物学专家 具有良好的培训医生-科学家记录的成像专家将担任主要导师。丽莎·罗森博士， Kenneth克罗恩博士，正电子发射断层扫描（PET）成像专家; William Rooney博士，神经生物学磁共振成像（MRI）专家;和罗谢尔傅博士，专家 临床试验生物统计学家将担任共同导师。该项目建议巴拉哈斯博士进行进一步的培训 在临床前胶质母细胞瘤模型中，人胶质母细胞瘤PET/MRI临床试验的实施和管理， 肿瘤免疫学，研究伦理学，资助写作和生物统计学的前瞻性研究和正式 课程工作。OHSU拥有丰富的协作环境，致力于促进职业发展 早期教师的发展。巴拉哈斯博士将获得至少80%的受保护研究时间 使OHSU成为执行该计划的理想环境，以便过渡到独立资助的研究 事业长期的科学目标是确定胶质母细胞瘤治疗的创新生物标志物， 阻力神经炎症（假性进展）是有效治疗和预后的标志， 生存然而，假进展和复发性疾病似乎是相同的标准治疗钆 增强MRI（Gd-MRI）。缺氧免疫微环境的变化可以作为缺氧免疫微环境的生物标志物。 有效治疗和独特的假性进展发展特征。严重未满足的临床需求， 免疫应答评估是监测缺氧免疫微环境的能力。我们 通过追求两个具体目标来解决这一重大知识差距：1）定义胶质母细胞瘤免疫疗法- 通过11.75T Ferumoxytol（Fe）-MRI测定介导的先天免疫激活和杀肿瘤功效，以及2）确定 如果Ferumoxytol增强和缺氧体积是胶质母细胞瘤免疫治疗介导的成像特征， 临床试验中的假进展或真进展。临床前胶质母细胞瘤模型（aim 1）和人类 将进行临床试验（目标2）。总体假设是Gd和Fe增强的FMISO PET/MRI 可以评估负责免疫治疗功效的生物学特征。这种转化研究和 职业发展建议将支持在这一领域的多学科指导的早期阶段的调查员 研究直接解决开发延长生命的治疗方法的主要挑战， 原发性脑肿瘤;能够特异性监测治疗效果的成像生物标志物的验证。

ABSTRACT This K08 proposal describes a 5-year career development plan with the goal of supporting Dr. Ramon Francisco Barajas’ advancement to the role of independent early stage physician-scientist. Dr. Barajas has completed clinical training in Diagnostic Radiology and Neurological Radiology at the University of California, San Francisco and is currently Assistant Professor in the Departments of Radiology and Advanced Imaging Research Center at Oregon Health & Science University (OHSU). Edward Neuwelt MD, an expert in drug delivery and molecular imaging with a strong record of training physician-scientists, will serve as principle mentor. Lisa Coussens PhD, renowned tumor immunologist; Kenneth Krohn PhD, positron emission tomography (PET) imaging expert; William Rooney PhD, neurobiology magnetic resonance imaging (MRI) expert; and Rochelle Fu PhD, expert clinical trial biostatistician, will serve as co-mentors. This project proposes Dr. Barajas’ undertake further training in preclinical glioblastoma models, human glioblastoma PET/MRI clinical trial implementation and management, tumor immunology, research ethics, grant writing and biostatistics by means of prospective research and formal course work. OHSU has a rich and collaborative environment, with a strong commitment to promoting career development for early stage faculty. Dr. Barajas will be provided with at least 80% protected research time making OHSU an ideal setting to carry out this program for transitioning to an independently funded research career. The long-term scientific objective is to define innovative biomarkers of glioblastoma therapeutic resistance. Neuroinflammation (pseudoprogression) is a hallmark of effective therapy and prognostic of overall survival. However, pseudoprogression and recurrent disease appear identical by standard of care gadolinium enhanced MRI (Gd-MRI). Changes within the hypoxic immune microenvironment may serve as biomarkers of effective therapy and unique feature of pseudoprogression development. A critically unmet clinical need for immunotherapeutic response assessment is the ability to monitor the hypoxic immune microenvironment. We address this significant gap in knowledge by pursuing two specific aims: 1) Define glioblastoma immunotherapy- mediated innate immune activation and tumoricidal efficacy by 11.75T Ferumoxytol (Fe)-MRI, and 2) Determine if Ferumoxytol-enhancement and hypoxic volume are imaging profiles of glioblastoma immunotherapy-mediated pseudoprogression or true progression in a clinical trial. Preclinical glioblastoma models (aim 1) and human clinical trials (aim 2) will be undertaken. The overall hypothesis is that Gd- and Fe-enhanced FMISO PET/MRI can assess the biological features responsible for immunotherapy efficacy. This translational research and career development proposal will support a mentored early stage investigator in this area of multidisciplinary research to directly address the major challenges of developing life prolonging therapeutic approaches for primary brain tumors; the validation of imaging biomarkers capable of specifically monitoring therapeutic efficacy.