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

• 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
• 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

 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是癌症治疗的重大挑战，并限制了其有效性。克服这些挑战的一种非常有希望的治疗方法是使用溶瘤病毒，这种病毒只选择性地杀死癌细胞，而不损害周围正常细胞。溶瘤病毒可以在原位产生后代，这些后代扩散到整个肿瘤并到达远端的恶性细胞，因此是治疗多形性胶质母细胞瘤(GBM)等浸润性癌症的理想策略。此外，溶瘤病毒可以被改造成表达化疗药物，从而提供多模式、靶向的药物输送。最后，溶瘤病毒可以引起对病毒感染的肿瘤细胞的强烈免疫反应。然而，由于缺乏监测这些治疗策略的成功和成像肿瘤内病毒传递、复制和传播的方法，目前肿瘤溶解病毒疗法及其临床翻译的优化受到阻碍。我们建议开发和优化一种MRI报告基因，该基因可以被工程化为溶瘤病毒，并允许溶瘤病毒治疗的非侵入性成像。我们最近已经证明，编码富含赖氨酸蛋白(LRP)的人工基因工程的溶瘤单纯疱疹病毒(OHSV)在病毒感染的急性阶段由于酰胺可交换的赖氨酸质子而产生化学交换饱和转移(CEST)磁共振成像对比，显著高于感染对照、非LRP表达病毒的肿瘤获得的对照。然而，将CEST OHSV报告基因方法移植到临床用于OHSV治疗的纵向成像将需要在成像和报告基因技术方面进行改进。我们假设，具有更强的交换率特异性的改进的CEST MRI方法将使病毒感染和复制能够在整个卵巢肿瘤治疗过程中得到纵向监测。为了验证这一假设，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磁共振成像方法，分别选择性地成像快速交换的LRP酰胺质子和缓慢交换的内源性酰胺质子(目标2)。最后，我们将使用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)。