Targeting diffuse liver metastases with Herpes virus

用疱疹病毒靶向弥漫性肝转移

• 批准号: 7175448
• 负责人: KENNETH K TANABE
• 金额: $ 37.66万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-07 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7175448
• 关键词: Affect; Animals; Biopsy Specimen; Bystander Effect; Clinical Research; Clinical Trials; Cytosine deaminase; Development; Diffuse; Dopamine Receptor; Drug Kinetics; Engineering; Enzymes; Flucytosine; Fluorouracil; Funding; Gene Activation; Gene Expression; Herpesviridae; Herpesvirus 1; Human; Image; Invasive; Kinetics; Laboratory Finding; Liver; Liver neoplasms; Location; Magnetic Resonance Spectroscopy; Metabolic; Metastatic Neoplasm to the Liver; Methods; Molecular; Mus; Normal Cell; Oncolytic viruses; Pathway interactions; Patients; Positioning Attribute; Positron-Emission Tomography; Process; Prodrugs; Rapid Access to Intervention Development; Regulation; Reporter; Reporter Genes; Research; Resistance; Safety; Site; Techniques; Thymidine Kinase; Time; Tissues; Transgenes; Translating; Uracil phosphoribosyltransferase; Viral; Virion; Yeasts; cancer cell; chemotherapy; improved; in vivo; molecular imaging; mutant; neoplastic; neoplastic cell; oncolysis; pre-clinical; research study; response; therapeutic transgene; tumor; viral detection

DESCRIPTION (provided by applicant): Viral replication in tumor cells leads to their destruction, with release of progeny virion that infect adjacent cancer cells in a process referred to as viral oncolysis. Clinical trials of oncolytic viruses have demonstrated both safety and potential efficacy of this approach. We have conducted research in the prior funding period demonstrating the utility of Herpes simplex virus 1 (HSV-1) mutants for viral oncolysis of liver tumors. We characterized regulation of HSV-1 replication at the molecular level, and used this information to 1) genetically engineer HSV-1 mutants that when introduced intravascularly into the liver replicate preferentially in liver metastases rather than normal cells; 2) express therapeutic transgenes such as prodrug activation genes (e.g. cytosine deaminase); 3) enhance survival of animals with diffuse liver tumors following intravascular delivery. Intratumoral conversion of 5-FC to 5-FU by the yeast cytosine deaminase transgene when added to HSV-1 oncolysis enhances efficacy. We have taken the most significant laboratory findings and moved them into clinical trials for patients with liver tumors with the assistance of the NCI Rapid Access to Intervention Development (RAID) program. We propose projects for this competing renewal application that expand on findings and observations made during the previous funding period. We propose to elucidate mechanisms of interaction between prodrug bioactivation and HSV-1 oncolysis. Positron emission tomography (PET) has been used to examine gene expression; however, we will develop PET to quantitatively assess viral replication. Presently, detection of viral replication requires sampling (biopsy) of tissues for molecular analyses. Because these techniques are invasive, cumbersome, and non-quantitative, they are not useful in human clinical trials of HSV-1 oncolysis. Accordingly there exists a strong rationale to develop minimally invasive imaging methods to quantitatively assess sites of HSV-1 replication. Successful development of quantitative imaging of viral replication will improve the quality of both preclinical and clinical studies of HSV-1 oncolysis. In Specific Aim 1, we will define interactions between intracellular conversion of 5-FC to 5-FU via the yeast cytosine deaminase transgene, HSV-1 replication, and anti-neoplastic efficacy. In Specific Aim 2, we will compare the dopamine receptor and thymidine kinase enzyme as reporters to quantitatively image viral replication with PET. We will co-register quantitative PET imaging of viral replication with imaging of tumor metabolic activity to simultaneously assess viral replication and anti-neoplastic response. We will also use [19F] magnetic resonance spectroscopy (MRS) to image cytosine deaminase transgene function. We are in position to directly translate observations from these experiments into clinical trials.

描述（由申请人提供）：肿瘤细胞中的病毒复制导致其被破坏，并释放子代病毒粒子，在称为病毒溶瘤的过程中感染邻近的癌细胞。溶瘤病毒的临床试验已经证明了这种方法的安全性和潜在功效。我们在之前的资助期间进行了研究，证明了单纯疱疹病毒 1 (HSV-1) 突变体在肝肿瘤病毒溶瘤中的效用。我们在分子水平上表征了 HSV-1 复制的调节，并利用这些信息来 1) 对 HSV-1 突变体进行基因工程改造，当将其引入血管内至肝脏时，该突变体优先在肝转移细胞而不是正常细胞中复制； 2) 表达治疗性转基因，例如前药激活基因（例如胞嘧啶脱氨酶）； 3) 提高血管内递送后患有弥漫性肝肿瘤的动物的存活率。当添加到 HSV-1 溶瘤中时，酵母胞嘧啶脱氨酶转基因可在瘤内将 5-FC 转化为 5-FU，从而增强疗效。在 NCI 快速干预开发 (RAID) 计划的协助下，我们取得了最重要的实验室发现，并将其转移到针对肝肿瘤患者的临床试验中。我们为这一竞争性更新申请提出项目，扩展了上一个资助期间的发现和观察结果。我们建议阐明前药生物激活和 HSV-1 溶瘤之间相互作用的机制。正电子发射断层扫描（PET）已用于检查基因表达；然而，我们将开发 PET 来定量评估病毒复制。目前，病毒复制的检测需要对组织进行取样（活检）以进行分子分析。由于这些技术具有侵入性、繁琐且非定量，因此它们在 HSV-1 溶瘤的人体临床试验中没有用处。因此，开发微创成像方法来定量评估 HSV-1 复制位点是有充分理由的。病毒复制定量成像的成功开发将提高 HSV-1 溶瘤临床前和临床研究的质量。在具体目标 1 中，我们将定义通过酵母胞嘧啶脱氨酶转基因在细胞内将 5-FC 转化为 5-FU、HSV-1 复制和抗肿瘤功效之间的相互作用。在具体目标 2 中，我们将比较多巴胺受体和胸苷激酶作为报告基因，以使用 PET 对病毒复制进行定量成像。我们将把病毒复制的定量 PET 成像与肿瘤代谢活动的成像结合起来，以同时评估病毒复制和抗肿瘤反应。我们还将使用 [19F] 磁共振波谱 (MRS) 对胞嘧啶脱氨酶转基因功能进行成像。我们能够将这些实验的观察结果直接转化为临床试验。