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A CEST-MRI Reporter Gene for Image Guided Oncolytic Virotherapy

用于图像引导溶瘤病毒治疗的 CEST-MRI 报告基因

基本信息

批准号：
9918257
负责人：
CHRISTIAN T FARRAR
金额：
$ 39.09万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-05-15 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9918257
关键词：
3-Dimensional Acute Aggressive behavior Amides Apoptosis Area Biological Biological Markers Biological Response Modifier Therapy Brain Neoplasms Cell Proliferation Chemicals Clinic Clinical Clinical Research Clinical Trials Detection Distal Distant Drug Delivery Systems Drug Targeting Effectiveness Engineered Gene Engineering Excision Frequencies Gene Proteins Glioblastoma Goals Grant Histologic Histology Image Immediate-Early Genes Immune response Inflammation Label Lysine Magnetic Resonance Imaging Malignant Neoplasms Measures Methods Modeling Monitor Mus Nature Normal Cell Oncogenic Viruses Oncolytic Oncolytic viruses Operative Surgical Procedures Physics Physiologic pulse Proteins Protons Reporter Reporter Genes Resected Sensitivity and Specificity Site Specificity Synthetic Genes Techniques Technology Testing Therapeutic Therapeutic Agents Toxic effect Translating Translations Treatment Efficacy Viral Viral Genes Virotherapy Virus Virus Diseases Virus Replication cancer cell cancer invasiveness cancer therapy chemotherapy clinical translation clinically relevant image guided imaging modality improved multimodality neoplastic cell non-invasive imaging non-invasive monitor novel novel imaging technology oncolytic herpes simplex virus oncolytic virotherapy promoter protein expression public health relevance radio frequency serial imaging success therapy outcome tumor

项目摘要

DESCRIPTION (provided by applicant): The highly invasive nature of many cancers and the toxicity of most systemic chemotherapies represent significant challenges for cancer therapies and limit their effectiveness. A very promising therapeutic approach for overcoming these challenges is the use of oncolytic viruses that selectively kill only cancer cells, while sparing te surrounding normal cells. Oncolytic viruses can generate progeny on-site that spread throughout the tumor and reach distal malignant cells, thus representing an ideal strategy for treating invasive cancers such as glioblastoma multiforme (GBM). In addition, oncolytic viruses can be engineered to express chemotherapeutics and thereby provide multimodal, targeted drug delivery. Finally, oncolytic viruses can elicit a strong immune response against viral infected tumor cells. However, the optimization of oncolytic virotherapies and their clinical translation is currently hindered by the lack of methods to monitor the success of these therapeutic strategies and image intratumoral viral delivery, replication and spread. We propose to develop and optimize a MRI reporter gene that can be engineered into oncolytic viruses and allow for the non-invasive imaging of oncolytic virotherapy. We have recently demonstrated that an oncolytic Herpes Simplex Virus (oHSV) engineered with an artificial gene encoding for a Lysine-Rich Protein (LRP) generated Chemical Exchange Saturation Transfer (CEST) MRI contrast, due to the amide exchangeable lysine protons, at acute stages of viral infection that was significantly higher than the contrast obtained from tumors infected with control, non-LRP expressing virus. Translation of the CEST oHSV reporter gene method to the clinic for longitudinal imaging of oHSV therapy will, however, require improvements in the imaging and reporter gene technology. We hypothesize that improved CEST MRI methods with greater exchange rate specificity will enable viral infection and replication to be monitored longitudinall throughout OV tumor therapy. To test this hypothesis we will first quantify the endogenous tumor CEST contrast and proton exchange rate during oHSV therapy (Aim 1). Next we will optimize Frequency Labeled Exchange Transfer (FLEX) and Variable Delay Multi-Pulse (VDMP) CEST MRI methods to selectively image the fast exchanging LRP amide protons and the slow exchanging endogenous amide protons, respectively (Aim 2). Finally, we will use immediate early and late gene viral promoters to longitudinally image viral infection and replication, respectively, in clinically relevant mouse GBM tumor models (Aim 3).

描述（由申请人提供）：许多癌症的高度侵袭性和大多数全身化疗的毒性对癌症治疗提出了重大挑战并限制了其有效性。克服这些挑战的一种非常有前途的治疗方法是使用溶瘤病毒，它选择性地仅杀死癌细胞，同时不伤害周围的正常细胞。溶瘤病毒可以在现场产生后代，传播到整个肿瘤并到达远端恶性细胞，因此代表了治疗侵袭性癌症（如多形性胶质母细胞瘤（GBM））的理想策略。此外，溶瘤病毒可以被设计来表达化疗药物，从而提供多模式、靶向药物递送。最后，溶瘤病毒可以引发针对病毒感染的肿瘤细胞的强烈免疫反应。然而，目前溶瘤病毒疗法的优化及其临床转化由于缺乏监测这些治疗策略成功与否以及对瘤内病毒递送、复制和传播进行成像的方法而受到阻碍。我们建议开发和优化 MRI 报告基因，该基因可以被工程化到溶瘤病毒中，并允许溶瘤病毒疗法的非侵入性成像。我们最近证明，用编码富含赖氨酸的蛋白（LRP）的人工基因改造的溶瘤单纯疱疹病毒（oHSV）由于酰胺可交换赖氨酸质子而产生化学交换饱和转移（CEST）MRI对比度，在病毒感染的急性阶段，其显着高于从感染对照、非LRP表达病毒的肿瘤中获得的对比度。然而，将 CEST oHSV 报告基因方法转化为临床用于 oHSV 治疗的纵向成像将需要改进成像和报告基因技术。我们假设，改进的 CEST MRI 方法具有更高的汇率特异性，将使病毒感染和复制在整个 OV 肿瘤治疗过程中得到纵向监测。为了检验这一假设，我们将首先量化 oHSV 治疗期间的内源性肿瘤 CEST 对比度和质子交换率（目标 1）。接下来，我们将优化频率标记交换转移 (FLEX) 和可变延迟多脉冲 (VDMP) CEST MRI 方法，分别选择性地对快速交换的 LRP 酰胺质子和慢速交换的内源酰胺质子进行成像（目标 2）。最后，我们将使用立即早期和晚期基因病毒启动子分别在临床相关的小鼠 GBM 肿瘤模型中纵向成像病毒感染和复制（目标 3）。