Sindbis Vectors For Advanced Pancreatic Cancer Therapy

用于先进胰腺癌治疗的 Sindbis 载体

• 批准号: 7229427
• 负责人: DANIEL MERUELO
• 金额: $ 28.67万
• 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/7229427
• 关键词: Accounting; Animal Model; Animals; Apoptosis; Cancer Etiology; Cells; Cessation of life; Class; Data; Death Rate; Development; Diagnosis; Disease; Disseminated Malignant Neoplasm; Dose; Drug Kinetics; Europe; Generations; Goals; Human; Image; Imagery; Imaging Techniques; Immune response; Immune system; Immunocompetent; In Vitro; In complete remission; Incidence; Lead; Learning; Magnetic Resonance Imaging; Malignant neoplasm of pancreas; Mediating; Modality; Modeling; Monitor; Mus; Neoplasm Metastasis; Patients; Play; Reagent; Role; SCID Mice; Specificity; Testing; Therapeutic; Treatment Protocols; USSR; United States; Viral Vector; Work; base; cancer therapy; design; gene therapy; improved; in vivo; mouse model; neoplastic cell; novel; response; translational approach; tumor; vector

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，我们试图开发更好的载体和试剂，以改善胰腺癌的治疗。胰腺癌是美国癌症死亡的第五个主要原因，在美国，每年约29,000人死亡，欧洲每年50,000例死亡（不包括前苏联）。中位生存期为六个月或更短，诊断后五年中只有四个患者还活着。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。但是，人们普遍认为，直到向量具有靶向肿瘤细胞的能力，基因治疗才能成功。正如应用程序中所述，信德氏病毒载体可以在体内系统地靶向并特别感染肿瘤细胞。但是，他们需要进一步研究以增强这些能力。 为此，我们试图完成以下操作：（目标1）在两个不同的胰腺癌的小鼠模型中，使用多种成像方式，包括IVL，MRI，MICROCT，Microspect和Micropet，以监测体内的体内模型，靶向和抗肿瘤的特异性和特异性以及各种Sindbis Vectors（Aim In niged In Aid Aim In Aim 2）。 （AIM 2）生成合理设计的信德省向量，可以在AIM 1的两个动物模型中进行测试，以最大化向量靶向和功效。 AIM 2的目的是设计和开发Sindbis矢量，可以通过（a）（a）矢量已知的凋亡诱导潜力的组合，胰腺癌及其转移完全缓解，（b）它们编码的治疗有效负载，以及（c）其可自定义的靶向能力。如AIM 1所述，对新向量的靶向和功效的体内监测对于实现这一目标至关重要。 （目标3）检查免疫系统在免疫功能小鼠模型中对Sindbis-Vector介导的治疗的影响。此类研究将在AIM 2中创建的Sindbis矢量的设计，生成和选择中发挥作用。这样的研究将有助于指导AIM 2中创建的Sindbis向量的设计，生成和选择。