Sindbis Vectors For Advanced Pancreatic Cancer Therapy

描述（由申请人提供）：在本申请中，我们寻求开发将改善胰腺癌治疗的更好的载体和试剂。胰腺癌是美国癌症死亡的第五大原因，在美国每年约有29，000人死亡，在欧洲（不包括前苏联）每年约有50，000人死亡。中位生存期为6个月或更短，只有4%的患者在诊断后存活5年。因此，发病率和死亡率几乎相同。 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，基因治疗才能成功。如将在本申请中描述的，辛德毕斯病毒载体可以在体内全身靶向并特异性感染肿瘤细胞。但是，需要进一步研究，以提高这些能力。 （目的1）使用多种成像模式，包括IVIS、MRI、microCT、microSPECT和microPET，在胰腺癌的两种不同小鼠模型中体内监测各种辛德毕斯载体（在目的2中产生）的靶向程度和特异性以及抗肿瘤功效。(Aim 2）产生合理设计的辛德毕斯载体，其可以在目标1的两种动物模型中测试，目标是使载体靶向和功效最大化。目的2的目标是设计和开发辛德毕斯载体，其可以通过（a）载体的已知的诱导胰腺癌及其转移的潜力，（B）它们编码的治疗有效载荷，和（c）它们的可定制的靶向能力的组合来诱导胰腺癌及其转移的完全缓解。如目标1中所讨论的，体内监测新载体的靶向和功效对于实现这一目标至关重要。(Aim 3）在免疫活性小鼠模型中检查免疫系统对辛德毕斯载体介导的治疗的影响。这些研究将在目标2中创建的辛德毕斯载体的设计、生成和选择中发挥作用。(Aim 4）用辛德毕斯载体在免疫活性小鼠中进行药代动力学研究，以用于载体介导的治疗。这些研究将有助于指导目标2中创建的辛德毕斯载体的设计、生成和选择。

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.