Targeting diffuse liver metastases with Herpes virus

用疱疹病毒靶向弥漫性肝转移

基本信息

批准号：
7744646
负责人：
KENNETH K TANABE
金额：
$ 38.88万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-01-07 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7744646
关键词：
Affect Animals Biopsy Specimen Bystander Effect Clinical Research Clinical Trials Cytosine deaminase Deaminase Development Diffuse Dopamine Receptor Drug Kinetics Engineering Enzymes Flucytosine Fluorouracil Funding Gene Activation Gene Expression Herpesviridae Herpesvirus 1 Human Image 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 Regulation Reporter Reporter Genes Research Resistance Safety Site Techniques Thymidine Kinase Time Tissues Transgenes Translating Uracil phosphoribosyltransferase Viral Virion Yeasts cancer cell chemotherapy imaging modality improved in vivo minimally invasive molecular imaging mutant neoplastic neoplastic cell oncolysis pre-clinical programs research study response therapeutic transgene therapy development tumor viral detection

项目摘要

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 RapidAccess 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.

肿瘤细胞中的病毒复制导致其破坏，释放出感染的子代病毒粒子相邻癌细胞的过程称为病毒溶瘤。溶瘤病毒的临床试验证明了这种方法的安全性和潜在功效。此前我们曾进行过研究资助期证明单纯疱疹病毒 1 (HSV-1) 突变体在肝脏病毒溶瘤中的效用肿瘤。我们在分子水平上表征了 HSV-1 复制的调节，并利用该信息 1) 基因工程HSV-1突变体，当血管内引入肝脏时，该突变体会复制优先发生在肝转移细胞而不是正常细胞中； 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) 提高患有弥漫性肝肿瘤的动物的存活率血管内输送。酵母胞嘧啶脱氨酶转基因将 5-FC 瘤内转化为 5-FU 当添加到 HSV-1 中时，溶瘤作用可增强疗效。我们采取了最重要的实验室发现并在 NCI RapidAccess 的协助下将它们转移到针对肝肿瘤患者的临床试验中干预发展（RAID）计划。我们为这一竞争性更新应用提出项目，扩展研究结果和观察结果是在上一个资助期间完成的。我们建议阐明之间的相互作用机制前药生物激活和 HSV-1 溶瘤作用。正电子发射断层扫描（PET）已被用于检查基因表达；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。因为这些技术是侵入性的、繁琐的、非定量的，它们在人体临床试验中没有用处。 HSV-1 溶瘤作用。因此，开发微创成像方法有充分的理由定量评估 HSV-1 复制位点。病毒定量成像技术开发成功复制将提高 HSV-1 溶瘤临床前和临床研究的质量。在具体目标 1 中，我们将通过以下方式定义 5-FC 细胞内转化为 5-FU 之间的相互作用：酵母胞嘧啶脱氨酶转基因、HSV-1 复制和抗肿瘤功效。在具体目标 2 中，我们将比较多巴胺受体和胸苷激酶作为记者来定量成像病毒 PET 复制。我们将把病毒复制的定量 PET 成像与肿瘤成像结合起来代谢活动，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。我们在能够将这些实验的观察结果直接转化为临床试验。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Epidermal growth factor receptor inhibition attenuates liver fibrosis and development of hepatocellular carcinoma.

DOI：
10.1002/hep.26898
发表时间：
2014-04
期刊：
HEPATOLOGY
影响因子：
13.5
作者：
Fuchs, Bryan C.;Hoshida, Yujin;Fujii, Tsutomu;Wei, Lan;Yamada, Suguru;Lauwers, Gregory Y.;McGinn, Christopher M.;DePeralta, Danielle K.;Chen, Xintong;Kuroda, Toshihiko;Lanuti, Michael;Schmitt, Anthony D.;Gupta, Supriya;Crenshaw, Andrew;Onofrio, Robert;Taylor, Bradley;Winckler, Wendy;Bardeesy, Nabeel;Caravan, Peter;Golub, Todd R.;Tanabe, Kenneth K.
通讯作者：
Tanabe, Kenneth K.

Mouse model of carbon tetrachloride induced liver fibrosis: Histopathological changes and expression of CD133 and epidermal growth factor.