Spread of Replicating Adenovirus in Pancreatic Tumors

描述（由申请人提供）： 对导致癌症的细胞和分子机制的理解的增加导致了生物制剂将在癌症治疗中发挥越来越大的作用的期望。复制病毒在靶细胞内将其遗传“有效载荷”倍增至数千倍，然后在肿瘤内从细胞扩散到细胞的能力是在分子疗法开发中利用的重要特征。然而，在迄今为止的少数临床试验中，复制腺病毒仅取得有限的临床成功。间质在肿瘤的发展中起着非常重要的作用，尤其是在胰腺癌中，它通常具有强烈的间质反应。这一建议的基础是我们最近发表的工作，表明复制腺病毒可以在异种移植肿瘤中以高水平持续数周，而不会完全消除这些肿瘤。因此，该提议旨在了解复制型腺病毒如何与胰腺异种移植肿瘤内的肿瘤细胞、基质细胞和肿瘤生理环境相互作用。更好地了解这些因素可能会使改进复制腺病毒基因治疗载体的设计，以促进其在胰腺肿瘤中的传播和疗效。目的之一是确定是否基质细胞或基质成分限制复制腺病毒载体通过胰腺异种移植肿瘤的传播。第二个目标是确定肿瘤内的缺氧区域是否限制了腺病毒的复制。目标三将确定肿瘤血管的强度或渗透性是否影响胰腺异种移植肿瘤内的病毒分布和扩散，以及是否可以对其进行修改以获得治疗优势。目的四将确定异种移植肿瘤细胞或感染病毒在持续感染过程中是否发生变化，以及这些变化是否降低了复制型腺病毒载体的功效。

DESCRIPTION (provided by applicant): An increased understanding of the cellular and molecular mechanisms that lead to cancer, has lead to an expectation that biological agents will play an increasing role in cancer therapy. The ability of a replicating virus to multiply its genetic "pay-load" up to several thousand-fold within a target cell, and then spread from cell-to-cell within a tumor, is an important characteristic to be harnessed in the development of a molecular therapy. However, in the few clinical trials to date replicating adenoviruses have only achieved limited clinical success. It has also become apparent that stroma plays a very important role in the development of tumors, and particularly so in pancreatic cancer which often has an intense stromal response. The foundation for this proposal is our recently published work showing that replicating adenovirus can persist for several weeks at high level within xenograft tumors without totally eliminating these tumors. This proposal is therefore directed towards understanding how the replicating adenovirus interacts with tumor cells, stromal cells and the tumor physiologic environment within pancreatic xenograft tumors. A better understanding of these factors may enable improvements to be made in the design of replicating adenoviral gene therapy vectors to facilitate their spread and efficacy in pancreatic tumors. Aim one will determine if stromal cellular or matrix components limit the spread of replicating adenoviral vectors through pancreatic xenograft tumors. Aim two will determine if areas of hypoxia within the tumor limit adenoviral replication. Aim three will determine if the intensity or permeability of the tumor vasculature influences viral distribution and spread within pancreatic xenograft tumors, and whether this can be modified for therapeutic advantage. Aim four will determine if xenograft tumor cells or the infecting virus change during the course of a persistent infection, and if these changes reduce the efficacy of the replicating adenovirus vector.