Enhanced CRAd for Pancreatic Cancer

胰腺癌是最具侵袭性的恶性肿瘤之一，预后极差。 条件复制型腺病毒(CRAd)是治疗胰腺癌的一种很有前途的治疗方法。 到目前为止，CRAd临床试验已经确定了这些药物的安全性，并确定了它们目前的 限制。为了解决这些局限性，我们开发了一系列传染性增强的 启动子控制的CRAD导致一个候选基因(RGDCOXCRAdF)，该基因目前处于临床前阶段 用于临床试验的毒理学研究。 胰腺癌分子生物学的最新进展确定了几个值得研究的靶点 分子特征：K-RAS激活突变、人端粒酶(TERT)上调、间皮蛋白 过表达和COX-2诱导。除了靶点特异性，CRAd的治疗效果可能是 通过为它们配备胰腺癌的抗肿瘤效应器(例如干扰素-ND)来进一步增强 可溶性转化生长因子(TGF)受体)。我们提出了新一代胰腺癌CRAd 通过利用这一特定的分子特征来设计疾病选择性和治疗效力 疾病。 除了载体设计，与这种疾病的临床环境密切相关的模型将是 用于向量求值。在小鼠模型的背景下，我们将采用原位胰腺 肿瘤异种移植模型以及传统的异种皮下移植模型。作为另一位模特， 仓鼠同基因胰腺癌模型将为CRAd的生物学提供更深入的了解，因为 该系统允许在支持人腺病毒的免疫活性动物中进行各种评估 复制。此外，光学监控功能将被纳入矢量设计，以允许 病毒复制的非侵入性检测，因此CRAd生物学。最后，我们最近成立了 基于组织切片技术的CRAd功能分析将使我们能够评估患者的CRAD 保持组织完整性的材料。 我们方法的验证将为小说的快速临床翻译奠定基础 基于CRAd的胰腺癌有效治疗策略。

Pancreatic cancer is one of the most aggressive malignancies with a devastating prognosis. Conditionally replicative adenovirus (CRAd) is a promising therapeutic modality for pancreatic cancer. CRAd clinical trials to date have established the safety of these agents and identified their current limitations. To address these limitations, we have developed a series of infectivity-enhanced, promoter-controlled CRAds resulting in one candidate (RGDCOXCRAdF) which is currently in preclinical toxicological studies for clinical trial. Recent advancement in pancreatic cancer molecular biology has identified several target worthy molecular features: k-RAS activating mutation, human telomerase (TERT) upregulation, mesothelin overexpression, and Cox-2 induction. In addition to target specificity, CRAd therapeutic effect could be further augmented by outfitting them with anti-tumor effectors for pancreatic cancer (e.g., interferon-¿nd soluble-transforming growth factor (TGF)-feceptor). We propose a new generation pancreatic cancer CRAd design with disease selectivity and therapeutic potency by exploiting the specific molecular features of this disease. In addition to vector design, the models with close relevance to the clinical settings of this disease will be employed for vector evaluation. In the context of murine models, we will employ an orthotopic pancreatic cancer xenograft model as well as a conventional subcutaneous xenograft model. As another model, a hamster syngeneic pancreatic cancer model will provide deeper insight about the biology of CRAd because this system allows various assessments in immunocompetent animals supporting human adenoviral replication. Furthermore, optical monitoring capability will be incorporated into the vector design to allow non-invasive detection of viral replication and therefore CRAd biology. Lastly, our recent establishment of CRAd function analysis based on tissue slice technology would allow us to evaluate our CRAds in patient materials with maintained tissue integrity. The validation of our methods would establish the foundation for rapid clinical translation of a novel and effective CRAd-based strategy for the treatment of pancreatic cancer.