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

描述（由申请方提供）：本提案的最终目标是评价溶瘤病毒（OV）治疗后肿瘤微环境中诱导的变化，并评估这些变化如何影响OV治疗。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，最终目标是设计更好的治疗策略来对抗脑肿瘤。我的实验室一直在研究OV治疗后肿瘤分泌的血管生成蛋白（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，这种蛋白与肿瘤增殖、血管生成和化疗耐药性的增加有关。它的表达与神经胶质瘤、前列腺癌和乳腺癌的阴性预后标志物相关。除了其对肿瘤进展的影响外，我们的初步结果表明，它还可能有助于胶质瘤细胞在随后的复制中对OV感染产生抗性。在这项拨款申请中，我们将验证我们的发现，其诱导胶质瘤与多种不同的溶瘤病毒。我们将进一步评估这种蛋白对OV感染的影响，并最终构建和测试能够克服这种蛋白诱导的OV。项目简介：美国癌症协会预测将有12740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，因为它将阐明溶瘤病毒治疗后肿瘤生物学的变化。这些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有效的肿瘤治疗。

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.