CELLULAR PATHWAYS AFFECTING ONCOLYTIC VIRUS-HOST INTERACTIONS IN CANCER

影响癌症中溶瘤病毒与宿主相互作用的细胞途径

• 批准号: 9099084
• 负责人: Valery Zurabovich Grdzelishvili
• 金额: $ 44.53万
• 依托单位: UNIVERSITY OF NORTH CAROLINA CHARLOTTE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9099084
• 关键词: Academic Research Enhancement Awards; Adenocarcinoma Cell; Affect; Antiviral Agents; Cancer Etiology; Cancer Patient; Cell Death; Cell Line; Cessation of life; Characteristics; Combined Modality Therapy; Development; Drug Combinations; Future; Genes; Goals; Human; Immunocompetent; Immunodeficient Mouse; In Vitro; Interferons; Knowledge; Lead; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Modeling; Mus; NF-kappa B; Neoplasm Metastasis; North America; Oncolytic; Oncolytic viruses; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Performance; Phase I Clinical Trials; Phase III Clinical Trials; Phenotype; Predisposition; Primary carcinoma of the liver cells; Publishing; Resistance; Role; Safety; Signal Transduction; Survival Rate; System; Testing; Tissues; Treatment Protocols; United States; Vesicular stomatitis Indiana virus; Virus; Virus Diseases; Virus Replication; Work; antitumor effect; base; cancer therapy; cellular targeting; clinically relevant; improved; in vivo; innovation; killings; neoplastic cell; novel; oncolysis; oncolytic Vesicular Stomatitis Virus; oncolytic virotherapy; outcome forecast; pancreatic cancer cells; permissiveness; preclinical study; public health relevance; rapid growth; research study; resistance mechanism; small molecule inhibitor; success; trait; treatment strategy; tumor; virus host interaction

 DESCRIPTION (provided by applicant): Pancreatic cancers, about 95% of which are pancreatic ductal adenocarcinoma (PDAC), have the worst prognosis of all cancers and will soon be the second leading cause of cancer-related deaths in the United States. Current treatment regimens clearly fail to benefit patient survival. Oncolytic virotherapy is a relatively new anticancer approach that utilizes replication-competent viruses to specifically infect and kill tumor cells. Vesicular stomatitis virus (VSV) is one such oncolytic virus (OV) and is already in a phase I clinical trial against hepatocellular carcinoma. Our recent studies demonstrated that VSV is effective against the majority of tested human PDAC cell lines, both in vitro and in vivo. However, we found that some PDAC cell lines are resistant to VSV infection, replication and virus-mediated oncolysis, largely due to the constitutive expression of antiviral genes. Our goal is to better understand and target PDAC cellular pathways determining the success of VSV- based OV therapy and to develop rational combination therapy approaches to enhance OV efficacy and/or overcome resistance to OVs. The proposed experiments are based on our recently published work and preliminary studies that analyzed VSV against a number of PDAC cell lines in vitro and in vivo, made an initial characterization of PDAC cells lines in regard to their general cellular characteristics and permissiveness to VSV, and identified small molecule inhibitors dramatically improving VSV performance in PDAC cells. In Aim 1, we will identify and target cellular factors leading to the constitutive expression of antiviral genes in PDAC cell line resistant to VSV; identify specific antiviral genes responsible for resistance of PDAC cell lines t VSV; and investigate how development of chemoresistance affects permissiveness of PDAC cells to VSV. In Aim 2, we will test in vivo VSV in combination with small molecule inhibitors shown in our preliminary studies to successfully down-regulate antiviral genes and stimulate VSV replication and oncolysis. Importantly, both aims will evaluate how these novel combination approaches affect oncoselectivity and safety of VSV-based OV therapy. Our studies will develop a more effective VSV oncolytic therapy, broaden the spectrum of PDAC phenotypes to which this treatment can be successfully applied, and will lead to development of prescreening approaches to identify cancer patients who will be responsive to specific OV treatments. While this proposal is focused on VSV against PDAC, it will define cellular factors and pathways likely affecting other OVs and tumor systems.

 描述（由申请人提供）：胰腺癌，其中约95%是胰腺导管腺癌（PDAC），在所有癌症中预后最差，很快将成为美国癌症相关死亡的第二大原因。目前的治疗方案显然不能使患者存活。溶瘤病毒疗法是一种相对较新的抗癌方法，它利用具有复制能力的病毒特异性地感染和杀死肿瘤细胞。 肿瘤细胞水泡性口炎病毒（VSV）就是这样一种溶瘤病毒（OV），并且已经处于针对肝细胞癌的I期临床试验中。我们最近的研究表明，VSV是有效的对大多数测试的人PDAC细胞系，在体外和体内。然而，我们发现一些PDAC细胞系对VSV感染、复制和病毒介导的溶瘤具有抗性，这主要是由于抗病毒基因的组成型表达。我们的目标是更好地理解和靶向决定基于VSV的OV治疗成功的PDAC细胞途径，并开发合理的联合治疗方法以增强OV疗效和/或克服对OV的耐药性。提出的实验是基于我们最近发表的工作和初步研究，分析VSV对一些PDAC细胞系在体外和体内，初步表征PDAC细胞系的一般细胞特性和宽容的VSV，并确定小分子抑制剂显着提高VSV性能的PDAC细胞。在目标1中，我们将确定和目标的细胞因子导致的抗病毒基因的组成型表达的PDAC细胞系耐VSV;确定特定的抗病毒基因负责的PDAC细胞系耐VSV;和调查如何发展的耐药性影响的PDAC细胞的宽容VSV。在目标2中，我们将在体内测试VSV与我们的初步研究中显示的小分子抑制剂组合，以成功下调抗病毒基因并刺激VSV复制和溶瘤。重要的是，这两个目标将评估这些新的组合方法如何影响基于VSV的OV治疗的肿瘤选择性和安全性。我们的研究将开发一种更有效的VSV溶瘤疗法，拓宽这种治疗可以成功应用的PDAC表型谱，并将导致开发预筛选方法来识别对特定OV治疗有反应的癌症患者。虽然该提案的重点是针对PDAC的VSV，但它将定义可能影响其他OV和肿瘤系统的细胞因子和途径。