Sindbis Vectors For Advanced Pancreatic Cancer Therapy

用于先进胰腺癌治疗的 Sindbis 载体

• 批准号: 6908073
• 负责人: DANIEL MERUELO
• 金额: $ 30.23万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6908073
• 关键词: SCID mouse; Sindbis virus; apoptosis; bioimaging /biomedical imaging; computed axial tomography; disease /disorder model; gene delivery system; immune response; magnetic resonance imaging; metastasis; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; nonhuman therapy evaluation; pancreas neoplasms; pharmacokinetics; positron emission tomography; single photon emission computed tomography

DESCRIPTION (provided by applicant): In this application we seek to develop better vectors and reagents that will improve the therapy of pancreatic cancer. Pancreatic cancer is the fifth leading cause of cancer death in the US and accounts for approximately 29,000 deaths per year in the United States and 50,000 deaths per year in Europe (excluding the former USSR). Median survival is six months or less, and only four percent of patients are alive five years after diagnosis. Thus, incidence and death rates are virtually identical. One approach to the treatment of this devastating disease is gene therapy. However, it is widely believed that gene therapy will not succeed until vectors are endowed with the ability to target tumor cells. As will be described in the application, Sindbis viral vectors can systemically target and specifically infect tumor cells in vivo. However, they require further study to enhance these capabilities. To do so we seek to accomplish the following: (Aim 1) To use multiple imaging modalities, including IVlS, MRI, microCT, microSPECT, and microPET to monitor in vivo, in two different mouse models of pancreatic cancer, the extent and specificity of targeting and antitumor efficacy of various Sindbis vectors (generated in Aim 2). (Aim 2) To generate rationally designed Sindbis vectors that can be tested in the two animals models of Aim 1, with the goal of maximizing vector targeting and efficacy. The goal of Aim 2 is to design and develop Sindbis vectors that can induce complete remission in pancreatic cancers and their metastases through a combination of (a) the vector's known apoptosis-inducing potential, (b) the therapeutic payload they encode, and (c) their customizable targeting capabilities. In vivo monitoring of the targeting and efficacy of the new vectors, as discussed in Aim 1, will be critical to achieving this goal. (Aim 3) To examine the effects of the immune system on Sindbis-vector mediated therapy in an immunocompetent mouse model. Such studies will play a role in the design, generation and selection of Sindbis vectors created in Aim 2. (Aim 4) To perform pharmacokinetic studies with the Sindbis vectors to be used for vector-mediated therapy in immunocompetent mice. Such studies will help guide the design, generation and selection of Sindbis vectors created in Aim 2.

描述（由申请人提供）：在本申请中，我们寻求开发更好的载体和试剂来改善胰腺癌的治疗。胰腺癌是美国癌症死亡的第五大原因，每年导致美国约 29,000 人死亡，欧洲（不包括前苏联）每年约 50,000 人死于胰腺癌。中位生存期为六个月或更短，只有百分之四的患者在诊断后五年内还活着。因此，发病率和死亡率实际上是相同的。 治疗这种毁灭性疾病的一种方法是基因治疗。然而，人们普遍认为，只有赋予载体靶向肿瘤细胞的能力，基因治疗才会成功。如本申请中将描述的，辛德比斯病毒载体可以系统地靶向并特异性地感染体内肿瘤细胞。然而，他们需要进一步的研究来增强这些能力。 为此，我们力求实现以下目标：（目标 1）使用多种成像方式，包括 IVLS、MRI、microCT、microSPECT 和 microPET，在两种不同的胰腺癌小鼠模型中体内监测各种 Sindbis 载体（在目标 2 中生成）的靶向程度和特异性以及抗肿瘤功效。 （目标 2）生成合理设计的 Sindbis 载体，可以在目标 1 的两种动物模型中进行测试，以最大限度地提高载体的靶向性和功效。 Aim 2 的目标是设计和开发 Sindbis 载体，通过结合 (a) 载体已知的细胞凋亡诱导潜力、(b) 它们编码的治疗有效负载和 (c) 其可定制的靶向能力，可以诱导胰腺癌及其转移的完全缓解。正如目标 1 中所讨论的，对新载体的靶向和功效进行体内监测对于实现这一目标至关重要。 （目标 3）在免疫功能正常的小鼠模型中检查免疫系统对 Sindbis 载体介导的治疗的影响。此类研究将在目标 2 中创建的 Sindbis 载体的设计、生成和选择中发挥作用。（目标 4）使用 Sindbis 载体进行药代动力学研究，用于免疫活性小鼠的载体介导的治疗。此类研究将有助于指导目标 2 中创建的 Sindbis 载体的设计、生成和选择。