Specific elimination of tumor stem cells using oncolytic viruses

使用溶瘤病毒特异性消除肿瘤干细胞

• 批准号: 222319775
• 负责人: Professor Dr. Christian Buchholz
• 金额: --
• 依托单位: Neurochirurgische Klinik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/222319775?language=en
• 关键词: Specific; elimination; tumor; stem; cells

Within tumor tissue a small fraction of cells has been demonstrated to behave like stem cells. These so called tumor stem cells have been described to reinitiate tumors and to even generate tumor vasculature. Surface markers such as CD133 are being used to identify and enrich tumor stem cells. CD133-positive tumor cells in hepatocellular cancer and glioblastoma are rare in tumor tissue but have a high potential for tumor initiation and were described to be resistant against radio- and chemotherapy. Anti-tumoral drugs targeted to tumor stem cells are therefore highly desirable.The applicants group has developed unique methods to achieve the retargeting of oncolytic viruses to any cell type and cellular surface receptor of choice. Towards the goals of this proposal, the applicants group generated for the first time an oncolytic virus that uses CD133 as receptor for cell entry. This virus termed MV-CD133 has been derived from measles virus (MV) and infects and lyses selectively CD133-positive tumor cells. Initial studies in mice carrying subcutaneously growing human hepatocellular carcinoma cells showed that MV-CD133 is able to exert a strong anti-tumoral effect. Notably, MV-CD133 reduced tumor growth more efficiently than the parental measles virus which is currently investigated in numerous clinical trials for the treatment of different tumor entities. This proposal aims at generating a novel anti-tumoral agent with absolute specificity for CD133-positive tumor cells. Based on the relevance of CD133 as marker for tumor stem cells, MV-CD133 may be the first oncolytic virus that selectively infects and kills tumor stem cells. By now, a tumor stem cell specific virus has not been described for any type of oncolytic virus. Based on preliminary data, we hypothesize that CD133-targeting enhances the anti-tumoral potential of oncolytic viruses for the treatment of hepatocellular cancer (HCC). Beyond HCC, we will explore the activity of MV-CD133 against glioblastoma for which CD133 has been suggested as tumor stem cell marker as well. To further enhance the oncolytic activity of MV-CD133 we will arm the virus with suicide genes and extend its tropism to CD133-negative tumor cells. The anti-tumoral efficacy of the viruses will be quantified in cell killing assays and by monitoring tumor growth in different mouse tumor models. Special emphasis will be put on the evaluation of primary tumor cells containing varying degrees of CD133-positive cells for their ability to form tumors and metastases when the CD133-positive cells in these samples have been infected by the virus. The activity of MV-CD133 will also be assessed in multi-focal tumor models which are more relevant for clinical applications. We expect from this project an improved understanding of the relevance of CD133 as marker of tumor stem cells as well as the basis for a novel innovative strategy in tumor therapy.

在肿瘤组织中，有一小部分细胞表现得像干细胞。这些所谓的肿瘤干细胞被描述为重新启动肿瘤，甚至产生肿瘤血管系统。CD133等表面标记物正被用于识别和富集肿瘤干细胞。肝细胞癌和胶质母细胞瘤中的cd133阳性肿瘤细胞在肿瘤组织中是罕见的，但具有很高的肿瘤起始潜力，并且被描述为对放疗和化疗具有耐药性。因此，针对肿瘤干细胞的抗肿瘤药物是非常需要的。申请人小组已经开发出独特的方法来实现溶瘤病毒的重靶向任何细胞类型和细胞表面受体的选择。为了实现这一提议的目标，申请人小组首次产生了一种使用CD133作为细胞进入受体的溶瘤病毒。这种被称为MV- cd133的病毒来源于麻疹病毒（MV），并选择性地感染和裂解cd133阳性的肿瘤细胞。在携带皮下生长的人肝癌细胞的小鼠中进行的初步研究表明，MV-CD133能够发挥强大的抗肿瘤作用。值得注意的是，MV-CD133比亲本麻疹病毒更有效地降低肿瘤生长，目前在许多临床试验中研究了麻疹病毒治疗不同肿瘤实体。本研究旨在产生一种对cd133阳性肿瘤细胞具有绝对特异性的新型抗肿瘤药物。基于CD133作为肿瘤干细胞标志物的相关性，MV-CD133可能是第一个选择性感染和杀死肿瘤干细胞的溶瘤病毒。到目前为止，肿瘤干细胞特异性病毒尚未被描述为任何类型的溶瘤病毒。基于初步数据，我们假设cd133靶向增强了溶瘤病毒治疗肝细胞癌（HCC）的抗肿瘤潜能。除HCC外，我们将探讨MV-CD133对胶质母细胞瘤的活性，CD133也被认为是肿瘤干细胞标志物。为了进一步增强MV-CD133的溶瘤活性，我们将用自杀基因武装病毒，并将其趋向性扩展到cd133阴性的肿瘤细胞。病毒的抗肿瘤功效将通过细胞杀伤试验和通过监测不同小鼠肿瘤模型的肿瘤生长来量化。当这些样本中的cd133阳性细胞被病毒感染时，将特别强调对含有不同程度cd133阳性细胞的原发肿瘤细胞形成肿瘤和转移的能力的评估。MV-CD133的活性也将在与临床应用更相关的多灶肿瘤模型中进行评估。我们期望从这个项目中提高对CD133作为肿瘤干细胞标志物的相关性的理解，并为肿瘤治疗的新创新策略奠定基础。