Spread of Replicating Adenovirus in Pancreatic Tumors

描述(由申请人提供)： 随着对导致癌症的细胞和分子机制的了解的增加，人们预计生物制剂将在癌症治疗中发挥越来越大的作用。复制病毒在靶细胞内将其基因“有效载荷”增加几千倍，然后在肿瘤内从一个细胞传播到另一个细胞的能力，是分子疗法开发中需要利用的一个重要特征。然而，到目前为止，在为数不多的临床试验中，复制腺病毒只取得了有限的临床成功。间质在肿瘤的发展中扮演着非常重要的角色，特别是在胰腺癌中，这一点也变得很明显，因为胰腺癌往往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瘤内高水平持续数周，而不会完全消除这些肿瘤。因此，这项建议旨在了解复制型腺病毒如何与胰腺移植瘤内的肿瘤细胞、间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有助于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。目的一将确定基质细胞或基质成分是否限制了复制性腺病毒载体通过胰腺移植瘤的扩散。目标二将确定肿瘤内的缺氧区是否限制了腺病毒的复制。目的三将确定肿瘤血管的强度或通透性是否会影响病毒在胰腺移植瘤内的分布和扩散，以及这种影响是否可以被修改以达到治疗的优势。目的确定在持续感染过程中，移植瘤细胞或感染病毒是否发生改变，以及这些改变是否会降低复制型腺病毒载体的效果。

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.