OV Therapy Induced Changes in Tumor Secretome and Their Impact on Therapy

描述(由申请人提供)：本提案的最终目标是评估溶瘤病毒(OV)治疗后肿瘤微环境的变化，并评估这些变化如何影响OV治疗。这些结果将有助于更好地了解OV治疗引起的肿瘤生物学变化，并将导致双臂肿瘤杀伤OV的发展。OV治疗肿瘤依赖于癌症特异性病毒的复制，导致肿瘤破坏，对邻近非肿瘤组织的毒性最小。使用具有复制能力的OVS治疗恶性胶质瘤患者的6项临床试验的结果表明，新方法相对安全，但对疗效的高期望仍未达到(1，2)。肿瘤的微环境越来越被认为是肿瘤进展和治疗反应的重要决定因素。我们正在研究溶瘤病毒(OV)治疗后肿瘤微环境的变化，最终目标是设计出更好的治疗策略来对抗脑瘤。我的实验室一直在研究OV治疗后肿瘤分泌的血管小体(分泌的血管生成蛋白)的变化。在我们的初步研究中，我们发现了一种分泌蛋白的显著增加，该蛋白与肿瘤增殖、血管生成和对化疗的耐药性有关。它的表达与胶质瘤、前列腺癌和乳腺癌的预后呈负相关。除了对肿瘤进展的影响外，我们的初步结果表明，在随后的几轮复制中，它还可能有助于胶质瘤细胞对OV感染的抵抗力的发展。在这份赠款提案中，我们将验证我们的发现，即它在多种不同的溶瘤病毒诱导脑胶质瘤中的作用。我们将进一步评估该蛋白对OV感染的影响，并最终构建和测试能够克服该蛋白诱导的OV。项目简介：美国癌症协会预测，将有12,740人死于脑/神经系统癌症。尽管经过几十年的研究，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方法，目前正在进行临床试验，以评估其对脑肿瘤的疗效。这项拨款中概述的拟议研究具有重要意义，因为它将阐明溶瘤病毒治疗后肿瘤生物学的变化。这一结果将促进我们对溶瘤病毒治疗后肿瘤生物学变化的理解。这将有助于将溶瘤病毒疗法转化为对肿瘤的有效治疗。

DESCRIPTION (provided by applicant): The ultimate goal of this proposal is to evaluate the changes induced in the tumor microenvironment upon treatment with oncolytic viruses (OV) and assess how these changes impact OV therapy. 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. 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 gliomas 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. We are investigating changes in the tumor microenvironment following oncolytic viral (OV) therapy, with the ultimate goal to devise better treatment strategies to combat brain tumors. My laboratory has been investigating changes in the tumor secreted angiotome (secreted angiogenic proteins) after OV therapy. In our preliminary studies, we have uncovered a significant increase in a secreted protein implicated in increased tumor proliferation, angiogenesis and resistance to chemotherapy. Its expression is correlated as a negative prognostic marker for gliomas, prostate, and breast cancer. Apart from its effect on tumor progression, our preliminary results indicate that it may also contribute to the development of resistance of glioma cells to OV infection in subsequent rounds of replication. In this grant proposal we will validate our findings of its induction in glioma with multiple different oncolytic viruses. We will further evaluate the effect of this protein on OV infection, and will finally construct and test an OV that can overcome the induction of this protein. PROJECT NARRATIVE: 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 changes in tumor biology upon oncolytic viral therapy. The results will advance our understanding of changes in tumor biology upon treatment with oncolytic viruses. This will help translate oncolytic viral therapy into an efficacious treatment for tumors.