Highly Specific and Efficient Vectors for Targeting Pancreatic Cancer

描述（由申请人提供）：在美国，胰腺癌仅是第31位最常见的癌症原因，但却是第4位最常见的癌症相关死亡原因。患者通常表现为晚期疾病，对化疗是出了名的难。尽管经过数十年的研究，PDAC的治疗干预在很大程度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一些临床成功，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一种基于分子靶向病毒载体的基因递送剂，用于治疗胰腺癌。为了最大限度地提高基因传递的安全性、效率和特异性，我们将采用结合转导和转录控制的策略，将腺相关病毒（AAV）靶向PDAC。多项目团队的博士。Kelly， French和Logsdon结合了来自不同科学领域的专业知识。Kelly博士发现了一种新的PDAC生物标志物（Plectin-1），以及一种针对该生物标志物的高亲和力和特异性肽。通过设计AAV衣壳来表达Plectin-1靶向肽，French博士已经证明了AAV对PDAC的转导靶向。此外，Logsdon博士还发现了一种pdac特异性启动子，可以对AAV进行转录控制。本提案采用多学科方法，跨越放射学、肿瘤学、病毒学和分子成像领域，设计一种针对原发性和转移性肿瘤的PDAC治疗方法。具体目标是：1)产生针对PDAC的转导和转录靶向的AAV载体。为此，我们寻求开发一种新的AAV载体，通过结合PTP转导靶向衣壳和PDAC限制性启动子的转录靶向，提高PDAC特异性和PDAC转导效率，而不是野生型AAV2。2) PDAC自杀基因治疗。在本研究中，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：一种凋亡诱导肽（KFAKFAK），一种分泌的ptp靶向KFAKFAK，用于测试旁观者效应和激活的Caspase 3。3)在严格的人类PDAC小鼠模型中全面分析转导和转录靶向自杀基因治疗。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的模型。我们还将利用一种经过验证的SPECT/CT显像剂来评估肿瘤负荷和肿瘤体积等终点。该联合研究/开发项目将产生新的基于aav的PDAC基因治疗系统，在临床前研究和转化为临床应用方面具有相当大的潜力。

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.