Sindbis Vectors For Advanced Pancreatic Cancer Therapy

描述(申请人提供)：在这项申请中，我们寻求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大原因，在美国每年约有2.9万人死亡，在欧洲(不包括前苏联)每年约有5万人死于胰腺癌。中位生存期为六个月或更短，只有4%的患者在确诊后五年内还活着。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疗法。然而，人们普遍认为，除非载体被赋予靶向肿瘤细胞的能力，否则基因治疗不会成功。正如将在申请中描述的那样，Sindbis病毒载体可以系统地靶向并特异性地感染体内的肿瘤细胞。然而，它们还需要进一步研究，以增强这些能力。 为此，我们试图实现以下目标：(1)使用多种成像手段，包括IVLS、MRI、microCT、microSPECT和microPET，在两个不同的胰腺癌小鼠模型中，在体内监测各种Sindbis载体(在Aim 2中产生)的靶向和特异性以及抗肿瘤效果。(目标2)产生可在目标1的两个动物模型中测试的合理设计的Sindbis载体，以最大限度地提高载体靶向性和有效性。目标2的目标是设计和开发Sindbis载体，该载体可以通过结合(A)该载体已知的凋亡诱导潜力、(B)其编码的治疗有效载荷以及(C)其可定制的靶向能力来诱导胰腺癌及其转移的完全缓解。正如目标1中所讨论的，体内监测新载体的靶向性和有效性将是实现这一目标的关键。(目的3)在具有免疫活性的小鼠模型中，检测免疫系统对Sindbis载体介导的治疗的影响。这些研究将在目标2(目标4)中创建的Sindbis载体的设计、生成和选择中发挥作用，以进行Sindbis载体的药代动力学研究，用于免疫活性小鼠的载体介导性治疗。这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。

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.