Highly Specific and Efficient Vectors for Targeting Pancreatic Cancer

描述（由申请人提供）：虽然胰腺癌仅为第31位最常见的癌症原因，但它是美国癌症相关死亡的第四位最常见原因。患者通常表现为晚期疾病，这是众所周知的化疗难治性。尽管进行了数十年的研究，但在PDAC的治疗干预方面基本上没有取得有意义的进展。在其他肿瘤适应症中，最近在靶向肿瘤递送治疗有效载荷方面取得了几项临床成功，第一个临床产品可能于2011年在美国获得批准。因此，本提案的总体目标是开发用于治疗胰腺癌的基于分子靶向病毒载体的基因递送剂。为了最大限度地提高安全性，基因递送的效率和特异性，我们将采用使用转导和转录控制的组合将腺相关病毒（AAV）靶向PDAC的策略。Kelly，French和Logsdon博士的多PI团队结合了来自不同科学领域的专业知识。Kelly博士发现了PDAC的一种新生物标志物（Plectin-1），以及一种靶向该生物标志物的高亲和力和特异性肽。通过改造AAV衣壳以表达Plectin-1靶向肽，French博士已经证明了AAV对PDAC的转导靶向。此外，Logsdon博士已经确定了一个PDAC特异性启动子，将允许AAV的转录控制。该提案采用跨放射学、肿瘤学、病毒学和分子成像领域的多学科方法，以设计针对原发性和转移性肿瘤的PDAC治疗。具体目的是：1）产生对PDAC特异的转导和转录靶向的AAV载体。在这个目标中，我们试图通过将PTP转导靶向衣壳与使用PDAC限制性启动子的转录靶向结合来开发一种新的AAV载体，该载体相对于野生型AAV 2具有改善的PDAC特异性和改善的PDAC转导效率。2)PDAC的自杀基因治疗。在这个目标中，我们将开发3种转录和转导靶向的AAV，当在胰腺癌细胞中表达时，它们将诱导细胞凋亡：细胞凋亡诱导肽（KFAKFAK）、分泌的PTP靶向的KFAKFAK以测试旁观者效应和活化的半胱天冬酶3。3)在人类PDAC的严格小鼠模型中转导和转录靶向自杀基因治疗的综合分析。在这里，我们将在3种不同的临床相关动物模型中评估新系统，包括原发性和转移性疾病模型。我们还将利用经过充分验证的SPECT/CT成像剂来评估肿瘤负荷和肿瘤体积等终点。联合研发项目将产生新的基于AAV的PDAC基因治疗系统，具有相当大的临床前研究和临床应用潜力。

DESCRIPTION (provided by applicant): While only the 31st most common cause of cancer, pancreatic cancer is the fourth most common cause of cancer-related death in the US. Patients typically present with advanced disease that is notoriously refractory to chemotherapy. Despite decades of research, meaningful advancements in the therapeutic intervention of PDAC have been largely absent. In other oncologic indications, there have been several recent clinical successes in targeted tumor delivery of therapeutic payloads, and the first clinical product will likely be approved in the US in 2011. Therefore, the overall goal of this proposal is to develop a molecularly targeted viral vector based gene delivery agent for the treatment of pancreatic cancer. In order to maximize safety, efficiency of gene delivery, and specificity, we will employ the strategy of targeting the adeno-associated virus (AAV) to PDAC using a combination of transductional and transcriptional control. The multi-PI team of Drs. Kelly, French and Logsdon combines expertise from diverse areas of science. Dr. Kelly has identified a novel biomarker of PDAC (Plectin-1) and also a high affinity and specificity peptide that targets that biomarker. By engineering the AAV capsid to express the Plectin-1 targeting peptide, Dr. French has already demonstrated transductional targeting of AAV to PDAC. Additionally, Dr. Logsdon has identified a PDAC-specific promoter that will allow transcriptional control of the AAV. This proposal takes a multidisciplinary approach that spans the fields of radiology, oncology, virology and molecular imaging to engineer a therapy for PDAC that targets both primary and metastatic tumors. The Specific Aims are: 1) Generation of transductionally and transcriptionally targeted AAV vectors specific for PDAC. In this aim, we seek to develop a novel AAV vector with improved PDAC-specificity and improved PDAC transduction efficiency over wild-type AAV2 by combining the PTP transductionally-targeted capsid with transcriptional targeting using PDAC-restricted promoters. 2) Suicide gene therapy for PDAC. In this Aim, we will develop 3 transcriptionally and transductionally targeted AAVs that will induce apoptosis when expressed in pancreatic cancer cells: an apoptosis inducing peptide (KFAKFAK), a secreted PTP-targeted KFAKFAK to test for bystander effects and activated Caspase 3. 3) Comprehensive analysis of transductionally and transcriptionally targeted suicide gene therapy in stringent mouse models of human PDAC. Here, we will evaluate the new system in 3 different clinically relevant animal models, including models with primary and metastatic disease. We will also utilize a well-validated SPECT/CT imaging agent to evaluate endpoints such as tumor burden and tumor volume. The combined research/development project will result in new AAV-based systems for PDAC gene therapy with considerable potential for both pre-clinical research and translation to clinical applications.