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。 连续复制型腺病毒（CRAd）是胰腺癌的一种有前途的治疗方式。 迄今为止的CRAD临床试验已经确定了这些药物的安全性，并确定了它们的当前用途。 局限性。为了解决这些局限性，我们开发了一系列增强感染力的， 启动子控制的CRAd产生一个候选物（RGDCOXCRAdF），其目前处于临床前阶段 临床试验的毒理学研究。 胰腺癌分子生物学的最新进展已经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、间皮素 过表达和考克斯-2诱导。除了靶点特异性，CRAd的治疗效果可能是 通过为它们配备用于胰腺癌的抗肿瘤效应物（例如，干扰素 可溶性转化生长因子（TGF）-受体）。我们提出新一代胰腺癌CRAd 设计疾病的选择性和治疗效力，通过利用这一特定的分子特征， 疾病 除了载体设计，与该疾病的临床环境密切相关的模型将被 用于向量评估。在鼠模型的背景下，我们将采用原位胰腺移植。 癌症异种移植模型以及常规皮下异种移植模型。作为另一种模式，A 仓鼠同系胰腺癌模型将提供关于CRAd生物学的更深入的了解， 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 复制的此外，光学监测能力将纳入矢量设计， 病毒复制的非侵入性检测以及因此的CRAd生物学。最后，我们最近成立的 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。 我们的方法的验证将为快速临床翻译一种新的， 有效的基于CRAD的胰腺癌治疗策略。

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.