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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：
9077832
负责人：
CHRISTIAN T FARRAR
金额：
$ 37.92万
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 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9077832
关键词：
Acute Aggressive behavior Amides Apoptosis Area Biological Biological Markers Biological Response Modifier Therapy Brain Neoplasms Cell Proliferation Chemicals Clinic Clinical Clinical Engineering Clinical Research Clinical Trials Detection Distal Distant Drug Delivery Systems Effectiveness Engineering Excision Frequencies Gene Proteins Glioblastoma Goals Grant Histology Image Imaging technology Immediate-Early Genes Immune response Inflammation Label Lysine Magnetic Resonance Imaging Malignant Neoplasms Measures Methods Modeling Monitor Mus Nature Normal Cell Oncolytic Oncolytic viruses Operative Surgical Procedures Physics Physiologic pulse Proteins Protons Reporter Reporter Genes Resected Sensitivity and Specificity Simplexvirus Site Specificity Staging 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 therapy chemotherapy clinically relevant image guided imaging modality improved killings neoplastic cell non-invasive imaging novel oncolytic virotherapy promoter protein expression public health relevance radio frequency 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).