Gene-Product Auto-Targeting to Tumor Vessels

描述(申请人提供)：靶向肿瘤中的基因产物对于系统性基因传递非常重要，因为使用最成功的系统性肿瘤靶向基因传递技术，只有一部分基因成功地传递到肿瘤中。更重要的是，一些基因产物，如IL-12，与留在血液或其他器官中相比，与留在血液或其他器官中相比，更有效。将基因产物靶向肿瘤的一个简单方法是产生并使用编码IL-12和肿瘤靶向小肽的融合基因。出乎意料的是，我们发现没有一个已知的肿瘤靶向多肽能增强IL-12诱导的抗肿瘤效果。然而，在目前的资助期间，我们发现了一种新的多肽VNTANST，当编码IL-12-VNTANST的融合基因被注射到远离肿瘤的肌肉中时，它可以促进IL-12蛋白在肿瘤中的积聚。使用基因治疗方法进行DNA传递，并使用融合基因产物IL-12-VNTANST进行肿瘤靶向(肿瘤靶向IL-12基因治疗已在多种肿瘤模型中显示出抑制肿瘤的巨大潜力。我们还发现，这种肿瘤靶向的IL-12(IL-12-VNTANST)与波形蛋白结合，波形蛋白是一种细胞内蛋白，在转移性肿瘤中增加。一个有趣的问题是，细胞外的IL-12-VNTANST如何与细胞内的蛋白质结合？值得注意的是，我们的初步研究表明，波形蛋白存在于恶性上皮细胞的细胞膜上。我们在这一新的应用中的目的是确定在一些转移的肿瘤细胞中膜波形蛋白的定位是否增加，从而在结合IL-12-VNTANST和增强IL-12的抗肿瘤效果方面具有重要作用。我们还将研究如何使用肿瘤靶向IL-12基因治疗来有效地使用这种靶向IL-12基因疗法来治疗不同器官的膜阳性转移肿瘤。我们推测，肿瘤靶向的IL-12-VNTANST基因治疗在治疗膜型波形蛋白阳性转移瘤方面具有很大的潜力。这项研究具有创新性，因为它可能明确地证实膜上波形蛋白的定位在肿瘤转移和促进拟议的靶向IL-12基因治疗中起着关键作用。膜Vimentin依赖的确认也将使我们能够在未来选择合适的荷瘤患者进行这种治疗，即所谓的个性化免疫治疗，这是新疗法的一个重要方向，也是我们努力的长期目标。

DESCRIPTION (provided by applicant): Targeting gene product in tumors is very important for systemic gene delivery because only a portion of genes are successfully delivered into tumors by using the most successful systemic tumor-targeted gene delivery technology. More importantly, some gene products such as IL-12 are more effective when co-localized with tumors, compared to staying in blood or other organs One simple approach to targeting gene product into tumors is to generate and use fusion genes encoding IL-12 and tumor-targeted mini-peptide. Unexpectedly, we found that none of the known tumor-targeted peptides boost IL-12-induced anti-tumor efficacy. In the current grant period, however, we discovered the novel peptide VNTANST, which boosts accumulation of IL-12 protein into tumors when a fusion gene encoding IL-12-VNTANST, was administered into muscles distant from the tumors. Using a gene therapy approach for DNA delivery and using a fusion gene product IL-12-VNTANST for tumor-targeting (tumor-targeted IL-12 gene therapy has shown great potential in inhibiting tumors in multiple tumor models. We also revealed that this tumor-targeting IL-12 (IL-12-VNTANST) binds to vimentin, a protein known as an intracellular protein and increased in metastatic tumors. An intriguing question is how the extracellular IL-12-VNTANST binds to an intracellular protein? Significantly, our preliminary study showed that vimentin is found on the cell membrane of malignant epithelial cells. Our objective in this renewal application is to determine whether membrane vimentin localization is increased in some of the metastatic tumor cells and thus has a significant role in binding to IL-12-VNTANST and boosting IL-12-anti-tumor efficacy. We will also examine how to effectively using this targeted IL-12 gene therapy for treating membrane positive metastatic tumors in various organs using tumor-targeted IL-12 gene therapy. We hypothesize that tumor-targeted IL-12- VNTANST gene therapy has a great potential for treating membrane vimentin positive metastatic tumors. The proposed study is innovative because it may definitively confirm that the membrane vimentin localization plays a key role for tumor metastasis and for boosting the proposed targeted IL-12 gene therapy. Confirmation of membrane vimentin dependence would also allow us selecting proper tumor-bearing patient in the future to perform this therapy, which is so called personalized immune therapy, an important direction of novel therapeutics and a long term of goal of our effort.