Enhanced CRAd for Pancreatic Cancer

描述（由申请人提供）：胰腺癌是最具侵袭性的恶性肿瘤之一。为了改变其毁灭性的预后，必须开发新的治疗方法。条件复制型腺病毒（CRAd）是胰腺癌的一种有前景的治疗方式。迄今为止，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局限性，我们的实验室正在开发更安全，更有效的CRAd用于治疗用途。在本研究中，我们计划通过利用胰腺癌自身的特异性分子特征，开发具有上级治疗效力和疾病选择性的新一代胰腺癌CRAds。我们已经开发了新一代载体修饰，可以提供不同水平的转导效率，胰腺癌分子生物学的最新进展已经确定了几个有价值的靶分子特征。为了更好的效力和靶特异性而工程化的CRAd将配备有改变胰腺癌肿瘤环境的抗肿瘤效应物。新的载体不仅将用小鼠皮下和原位异种移植模型进行测试，而且还将用与人类临床情况密切相关的模型进行测试。仓鼠同基因胰腺癌模型，允许人类腺病毒复制将提供更深入的了解CRAd生物学。基于组织切片技术的CRAd功能分析使我们能够评估患者材料中的CRAd。我们开发的非侵入性病毒复制监测能力将进一步加强这些评估。下一代CRAds的开发和分析将为胰腺癌提供具有临床意义的新疗法。公共卫生相关性：胰腺癌预后不良促使我们努力开发新的治疗方法。更有效和更安全的CRAds可以被塑造成临床有效的治疗剂。此外，临床相关模型中CRAD功能的详细分析将提供推进载体设计所需的关键信息。该项目的结果将导致胰腺癌的临床可用疗法。

DESCRIPTION (provided by applicant): Pancreatic cancer is one of the most aggressive malignancies. In order to change its devastating prognosis, a novel therapeutic approach must be developed. The conditionally replicative adenovirus (CRAd) is one such promising therapeutic modality for pancreatic cancer. CRAd clinical trials to date have established the safety of these agents and identified their current limitations, and our laboratory is developing safer and more potent CRAds for therapeutic use. In this proposal, we plan to develop of a new generation pancreatic cancer CRAds with superior therapeutic potency and disease selectivity by exploiting the specific molecular features of this disease itself. We have developed new generation vector modifications which can provide a different level of transduction efficiency, and recent advancements in pancreatic cancer molecular biology have identified several target-worthy molecular features. The CRAds engineered for better potency and target specificity will be outfitted with anti-tumor effectors modifying pancreatic cancer tumor environment. New vectors will be tested not only with mouse subcutaneous and orthotopic xenograft models but also with models showing close relevance to human clinical situations. A hamster syngeneic pancreatic cancer model which allows human adenoviral replication will provide deeper insight into CRAd biology. The CRAd function analysis based on tissue slice technology permits us to evaluate CRAds in patient materials. These assessments will be further strengthened by the non-invasive viral replication monitoring capability we have developed. The development and analysis of next-generation CRAds will precede a clinically meaningful and novel therapy for pancreatic cancer. PUBLIC HEALTH RELEVANCE: The poor prognosis for pancreatic cancer drives our effort to develop new therapeutic modalities. More potent and safer CRAds can be fashioned into a clinically effective therapeutics. Also, detailed analyses of CRAd functionality in clinically relevant models will provide the crucial information required to advance vector design. The outcome of this project will lead to a clinically usable therapeutics for pancreatic cancer.