Enhancing Viral Oncolysis with Vasculostatin Gene Delivery

描述（由申请方提供）：本提案的最终目标是了解表达Vstat 120的溶瘤病毒对OV增殖、肿瘤生物学和抗肿瘤疗效的贡献。这些结果将导致更好地理解OV治疗诱导的肿瘤生物学变化，并将导致双武装癌症杀伤OV的发展。肿瘤的OV治疗依赖于病毒的癌症特异性复制，导致肿瘤破坏，对邻近的非肿瘤组织具有最小的毒性。使用可复制OV治疗恶性胶质瘤患者的六项临床试验的结果表明，新的模式相对安全，但对疗效的高期望仍未得到满足（1，2）。肿瘤的微环境越来越被认为是其进展及其对治疗反应的重要决定因素。我的实验室最近创造了两种溶瘤病毒，带有抗血管生成基因。我们现在建议阐明这种血管生成抑制蛋白在病毒繁殖、胶质瘤生物学和OV疗效中的作用。 公共卫生相关性：美国癌症协会预测，将有12,740人死于脑/神经系统癌症。尽管有几十年的研究，恶性胶质瘤患者的预后仍然很差。溶瘤病毒疗法是一种实验性治疗，目前正在临床试验中评估其对脑肿瘤的疗效。这项资助中概述的拟议研究非常重要，因为它将阐明携带Vstat 120的溶瘤病毒对肿瘤微环境和OV疗效的影响。这些结果将有助于将溶瘤病毒疗法转化为有效的肿瘤治疗。

DESCRIPTION (provided by applicant): The ultimate goal of this proposal is to understand the contribution of Vstat120 expressing oncolytic viruses on OV propagation, tumor biology and anti-tumor efficacy. These results will lead to a better understanding of OV therapy induced changes in tumor biology and will lead to the development of a dually armed cancer killing OV. The OV treatment of tumors relies on cancer-specific replication of the virus leading to tumor destruction with minimal toxicity to adjacent non-neoplastic tissue. Results from six clinical trials using replication competent OVs to treat patients with malignant glioma have shown the new modality to be relatively safe, but high expectations of efficacy remain unmet (1, 2). The tumor's microenvironment is increasingly recognized as an important determinant for its progression and its response to therapeutics. My laboratory has recently created two oncolytic viruses, armed with an anti-angiogenic gene. We now propose to elucidate the role of this angiostatic protein in viral propagation, glioma biology and OV efficacy. PUBLIC HEALTH RELEVANCE: The American Cancer Society predicts that there will be 12,740 deaths due to cancers of the brain/nervous system. Despite decades of research prognosis for patients suffering from malignant gliomas remains poor. Oncolytic viral therapy is an experimental treatment which is currently being evaluated in clinical trials for efficacy against brain tumors. The proposed research outlined in this grant is highly significant because it will elucidate the impact of an oncolytic virus armed with Vstat120 on tumor microenvironment, and OV efficacy. The results will help translate oncolytic viral therapy into an efficacious treatment for tumors.