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（由适用提供）：许多癌症的高度侵入性和大多数全身化疗的毒性代表了癌症疗法的重大挑战，并限制了它们的有效性。克服这些挑战的一种非常有前途的疗法是使用溶瘤病毒选择性地杀死癌细胞，同时保留周围的正常细胞。溶瘤病毒可以产生分布在整个肿瘤中并进入不同恶性细胞的后代现场，从而代表了治疗侵入性癌症（如胶质母细胞瘤多形菌（GBM））的理想策略。此外，可以设计出溶瘤病毒以表达化学治疗剂，从而提供多模式的靶向药物递送。最后，溶瘤病毒可以引起针对病毒感染肿瘤细胞的强烈免疫反应。然而，目前缺乏监测这些治疗策略的成功和图像肿瘤内病毒递送，复制和扩散的方法，目前阻碍了溶瘤病毒疗法及其临床翻译的优化。我们建议开发和优化可以设计到溶瘤病毒中的MRI报告基因，并允许对溶瘤病毒疗法进行非侵入性成像。我们最近证明，通过编码赖氨酸蛋白（LRP）产生的化学交换饱和转移（CEST）MRI对比的人工基因设计的溶瘤疱疹病毒（OHSV），这是由于在病毒感染的急性感染中，与不受反对的抗相反的反应相比，由于可及时可交换的赖氨酸方案，因此，不弥代的赖氨酸方案。但是，将CEST OHSV报告基因方法转换为诊所进行OHSV治疗的纵向成像，将需要改进成像和报告基因技术。我们假设改善了具有更高汇率特异性的CEST MRI方法将使病毒感染和复制能够在整个OV肿瘤治疗中受到监测。为了检验该假设，我们将首先量化OHSV治疗期间的内源性肿瘤对比度和质子汇率（AIM 1）。接下来，我们将优化频率标记的交换转移（FLEX）和可变延迟多脉冲（VDMP）CEST MRI方法，以选择性地对快速交换LRP酰胺质子和慢速交换内源性酰胺质子进行成像（AIM 2）。最后，在临床相关的小鼠GBM肿瘤模型中，我们将立即使用早期和晚期基因病毒启动子分别使用纵向图像病毒感染和复制（AIM 3）。