Vector delivery to modify the brain tumor and its microenvironment

变形性胶质母细胞瘤(GBM)是最常见的原发性脑癌。尽管咄咄逼人 包括手术、放射治疗和化疗在内的治疗，复发的疾病几乎总是致命的。 溶瘤的单纯疱疹病毒载体(如G207)在治疗基底膜方面显示出一些希望。 几乎没有完整的回应，这一令人失望的结果很可能与载体不足有关 感染和生长，特别是在从肿瘤块迁移和侵袭的肿瘤细胞中 正常的脑组织。因此，项目3的中心目标是改进溶瘤载体的传递、复制 并在保持安全性和肿瘤特异性的同时传播。因为肿瘤微环境的变化 极大地影响病毒的生长，我们建议进一步武装这些溶瘤载体 改善载体分布、克服局部抗病毒反应并增强易感性的基因 与细胞凋亡机制有关。具体地说，我们建议：(一)探索其生长、扩散和抗肿瘤作用 高活性HSV-1株Kos溶瘤载体(KOV)非必需缺失的潜能 即刻提早(即)ICPO、ICP22和ICP47基因，(Ii)利用重组Kov载体 分泌表达抗血管生成活性的分泌型基质金属蛋白酶ADAMTS-8 在努力增加初始媒介分布和促进复制期间媒介传播的活动中， (3)研究能够表达VH1、BINL和显性阴性的重组KOV的使用 IKB(KBaM)作为干扰素-γ(IFNy)和吲哚-2，3-双加氧酶(IDO)抗病毒药物 和细胞因子诱导途径，以及(Iv)评估重组Kov的表达能力 (A)一种新的显性负性PKCE(DNP)，可阻断其抗凋亡功能，(B)caspase 8a至 启动凋亡级联反应和(C)优化的重组可溶性TRAIL(OrsTRAIL)诱导 肿瘤细胞凋亡。最终，我们的目的是创建一种强大的肿瘤溶解载体，利用 这些促进生长、抗肿瘤的功能结合在一起，将为这种形式的 神经胶质瘤治疗。这种新载体将与G207进行比较，以展示更好的抗肿瘤效果 回应。这种高度工程化的载体也将为更好地了解胶质瘤提供机会。 细胞生物学，与项目1合作，大大改进抗癌药物的使用，并协助 与项目2合作诱导肿瘤特异性免疫。我们的复制能力 基因载体应该在开发有效的多模式治疗方面发挥作用，这是一个重要的 我们项目资助的总体目标。

Glioblastoma mutliforme (GBM) is the most common form of primary brain cancer. Despite aggressive therapies including surgery, radiotherapy, and chemotherapy, recurrent disease is nearly always fatal. Oncolytic HSV vectors (e.g. G207) have shown some promise in the treatment of GBM however there have been few complete responses, a disappointing outcome most likely related to inadequate vector infection and growth, particularly among tumor cells that migrate from the tumor mass and invade normal brain tissue. Thus a central goal of Project 3 is to improve oncolytic vector delivery, replication and spread while maintaining safety and tumor specificity. Because changes in the tumor microenvironment greatly influence virus growth, we propose further to arm these oncolytic vectors with genes that improve vector distribution, overcome local anti-viral responses and enhance susceptibility to apoptotic mechanisms. Specifically, we propose to: (i) to explore the growth, spread and anti-tumor potential of a highly active HSV -1 strain KOS Oncolytic Vector (KOV) deleted for the non-essential immediate early (I.E.) genes ICPO, ICP22 and ICP47, (ii) to employ a recombinant KOV vector expressing a secreted matrix metalloproteinase protease (ADAMTS-8) with strong anti-angiogenic activity in an effort to increase initial vector distribution and to facilitate vector spread during replication, (iii) examine the use of a recombinant KOV capable of expressing VH1, binl and a dominant negative IKB (kBaM) as inhibitors of the interferon gamma (IFNy) and indoleamine 2,3-dioxygenase (IDO) antiviral and cytokine induction pathways and (iv) to evaluate the ability of recombinant KOV expressing (a) a novel dominant negative PKCe (DNP) that blocks its anti-apoptotic function, (b) caspase 8a to launch the apoptotic cascade and (c) an optimized recombinant soluble TRAIL (orsTRAIL) to induce tumor cell apoptosis. Ultimately, it is our intention to create a powerful oncolytic vector that exploits these combined growth-facilitating, anti-tumor functions that will set a new standard for this form of glioma therapy. This new vector will be compared to G207 to demonstrate improved anti-tumor responses. The highly engineered vector will also provide opportunities to better understand glioma cell biology, greatly improve the use of anti-cancer drugs in collaboration with Project 1 and assist the induction of tumor-specific immunity in collaboration with Project 2. Together our replication competent gene vectors should be useful in the development of an effective multi-modal therapy, an important overall goal of our program project grant.