Highly Specific and Efficient Vectors for Targeting Pancreatic Cancer

描述(申请人提供)：胰腺癌在美国癌症相关死亡原因中排名第四，仅在最常见的癌症原因中排名第31位。患者通常患有晚期疾病，众所周知，这种疾病对化疗无效。尽管进行了几十年的研究，但在PDAC的治疗干预方面仍缺乏有意义的进展。在其他肿瘤学适应症方面，最近在靶向肿瘤治疗有效载荷方面取得了几项临床成功，第一个临床产品很可能于2011年在美国获得批准。因此，本方案的总体目标是开发一种分子靶向的病毒载体为基础的基因递送剂，用于治疗胰腺癌。为了使基因传递的安全性、效率和特异性最大化，我们将采用靶向腺相关病毒(AAV)到PDAC的策略，使用转导和转录控制的组合。由凯利博士、弗兰奇博士和洛格斯顿博士组成的多PI团队结合了不同科学领域的专业知识。凯利博士已经确定了一种新的PDAC生物标记物(Plectin-1)，以及一种针对该生物标记物的高亲和力和特异性多肽。通过设计AAV衣壳来表达Plectin-1靶向多肽，弗兰奇博士已经证明了AAV对PDAC的转导靶向。此外，Logsdon博士已经确定了一种PDAC特异性启动子，它将允许对AAV进行转录控制。这项建议采用了跨放射学、肿瘤学、病毒学和分子成像领域的多学科方法来设计一种针对原发和转移肿瘤的PDAC治疗方法。其具体目的是：1)构建针对PDAC的转导和转录靶向AAV载体。在这一目标中，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起来，开发一种新型的AAV载体，该载体具有更好的PDAC特异性和比野生型AAV2更高的PDAC转导效率。2)PDAC的自杀基因治疗。为此，我们将开发3种转录和转导靶向的AAVs，它们在胰腺癌细胞中表达时将诱导细胞凋亡：凋亡诱导肽(KFAKFAK)，分泌的PTP靶向KFAKFAK以测试旁观者效应和激活Caspase 3)在严格的人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个不同的临床相关动物模型中评估新系统，包括原发和转移疾病模型。我们还将利用经过充分验证的SPECT/CT显像剂来评估终点，如肿瘤负荷和肿瘤体积。联合研究/开发项目将产生用于PDAC基因治疗的基于AAV的新系统，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.