Tropism Enhanced Oncolytic Adenovirus for the treatment of Brain Tumors

恶性脑肿瘤是最致命的人类癌症之一，中位生存期仅为一年。 然而，我们已经证明，Delta-24-RGD，一种新的，肿瘤选择性的，感染性增强的，复制能力强的， 我们小组开发的溶瘤病毒可能是一种有效的治疗胶质瘤的方法。德尔塔-24- RGD是独特的，因为它的肿瘤选择性是基于病毒E1 A基因的改变，这使得 它比以前的溶瘤腺病毒更具选择性和效力，并且由于添加了RGD， 在纤维球的基序，这增加了其对肿瘤细胞的感染性。事实上，临床前研究表明， Delta-24-RGD在动物模型中根除人类胶质瘤的能力，以及 计划于2007年1月开始对复发性恶性胶质瘤患者进行Delta-24-RGD治疗。这里我们 假设Δ-24-RGD在人神经胶质瘤中有效，且该功效可通过以下方式提高 将其与化疗剂结合，并通过利用人骨的肿瘤嗜性， 骨髓来源的间充质干细胞，以改善病毒输送。测试我们假设的具体目标 目标：1。确定Delta-24-RGD在胶质瘤中复制和扩散的程度 在患者体内原位。为了评估病毒感染、复制和原位扩散，治疗后胶质瘤 在我们的I期临床试验中，通过“整块”外科手术获得的患者标本将 检查以建立肿瘤中Delta-24-RGD分布模式的定性评估，和 将对从初始注射点开始的扩散距离进行定量评估。AIM 2. 确定Delta-24-RGD和替莫唑胺协同抗神经胶质瘤药物的程度 并对协同作用的潜在机制进行了研究。初步数据显示， Delta-24-RGD和替莫唑胺的组合导致显著的抗胶质瘤作用。我们假设这 增加的功效是由于腺病毒介导的DMA修复途径和G2阻滞的抑制 参与替莫唑胺耐药。这一目的的结果，包括DMA修复基因和细胞的表达， 将溶瘤腺病毒的周期修饰与从人类患者获得的数据进行比较 目的1中的样本，以确定腺病毒感染是否会导致产生有利的 体内替莫唑胺敏感性的条件。AIM 3.确定骨髓来源的程度 人骨髓间充质干细胞可以改善Delta-24-RGD向胶质瘤的递送。 初步数据表明，hMSC在体内全身注射后定位于神经胶质瘤，并且这一结果表明， 可以利用神经胶质瘤的嗜性来递送治疗剂。为了验证这一假设，体内研究 将进行以证明用Delta-24-RGD感染的hMSC能够在多大程度上 在全身注射后整合入人神经胶质瘤，并且能够根除脑肿瘤。

Malignant brain tumors are among the most deadly human cancers, with a median survival of only one year. However, we have shown that Delta-24-RGD, a new, tumor-selective, infectivity-augmented, replicationcompetent oncolytic virus developed by our group may be an effective treatment against gliomas. Delta-24- RGD is unique, because its tumor selectivity is based on an alteration of the viral E1A gene, which renders it more selective and potent than previous oncolytic adenoviruses, and because of the addition of an RGD motif in the fiber knob, which increases its infectivity of tumor cells. Indeed, preclinical studies demonstrated the capacity of Delta-24-RGD to eradicate human gliomas in animal models, and a Phase I clinical trial of Delta-24-RGD in patients with recurrent malignant gliomas is scheduled to begin in January 2007. Here we hypothesize that Delta-24-RGD will be efficacious in human gliomas, and this efficacy can be improved by combining it with chemotherapeutic agents and by exploiting the tumor tropic properties of human bone marrow-derived mesenchymal stem cells to improve viral delivery. The Specific Aims to test our hypothesis are: AIM 1. Determine the extent to which Delta-24-RGD can replicate in and spread through gliomas in situ in patients. In order to assess viral infection, replication, and spread in situ, post-treatment glioma specimens obtained by "en bloc" surgical procedures in patients enrolled in our Phase I clinical trial will be examined to establish qualitative assessments of the pattern of Delta-24-RGD distribution in the tumor, and quantitative assessments of the distance of spread from the initial point of injection will be made. AIM 2. Determine the extent to which Delta-24-RGD and temozolomide are synergistic anti-glioma agents and exam of the underlying mechanisms of the synergy. Preliminary data indicate that the combination of Delta-24-RGD and temozolomide results in a significant anti-glioma effect. We hypothesize that this increased efficacy is due to adenovirally-mediated inhibition of the DMA-repair pathways and the G2 arrest involved in temozolomide resistance. Results of this Aim, including expression of DMA repair genes and cell cycle modifications by oncolytic adenoviruses, will be compared with the data obtained from human patient samples in Aim 1 to ascertain whether adenovirus infection would result in the generation of favorable conditions for temozolomide sensitivity in vivo. AIM 3. Determine the extent to which bone marrowderived human mesenchymal stem cells can improve the delivery of Delta-24-RGD to glioma. Preliminary data demonstrate that hMSC localize to gliomas after systemic injection in vivo and that this tropism for gliomas can be exploited to deliver therapeutic agents. To test this hypothesis, in vivo studies will be undertaken to demonstrate the extent to which hMSCs infected with Delta-24-RGD are capable of integrating into human gliomas after systemic injection, and are capable of eradicating brain tumors.