LuIII parvovirus targets glioma

LuIII细小病毒靶向神经胶质瘤

基本信息

批准号：
8643779
负责人：
ANTHONY N VAN DEN POL
金额：
$ 33.51万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8643779
关键词：
Address Adult Animal Model Antiviral Agents Antiviral Response Attenuated Brain Brain Neoplasms Cell Transplants Cells Cessation of life Clinical Clinical Trials Data Diagnosis Diagnostic Gene Expression Profile Gene Mutation Genes Genetic Glioblastoma Glioma Goals Human Infection Injection of therapeutic agent Interferons Invaded Lead Life Lung Malignant - descriptor Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of lung Messenger RNA Mutation Neoplasm Metastasis Neuroglia Neurons Normal Cell Oncolytic Oncolytic viruses Operative Surgical Procedures Outcome PTPN11 gene Parvovirus Patients Performance Primary Brain Neoplasms Quality of life Radiation Recurrence Reporter Reporting Safety Second Primary Cancers Slice Source Staining method Stains System Testing Tissues Toxic effect Up-Regulation Viral Viral Antigens Virus Virus Diseases Work base cancer cell deep sequencing exome killings melanoma neoplastic cell oncolysis outcome forecast prevent public health relevance rat parvovirus research study response transcriptome sequencing tumor

项目摘要

DESCRIPTION (provided by applicant): Glioblastomas are aggressive and invasive brain tumors that generally lead to death within a year of diagnosis. No cure is available, and current treatments prolong life by only a few months, often at the expense of quality of life. A number of parvoviruses have been reported to show oncolytic potential against cancer cells, and a rat parvovirus, H-1, is currently in clinical trials to treat glioma patients. In our initial work screning a large number of parvoviruses, we found one relatively obscure parvovirus, LuIII, that performed substantially better than any of the others tested, including H-1, and was the only parvovirus tested that successfully killed multiple human gliomas. LuIII appears safe in the brain, and does not target or kill neurons and shows minimal infection of normal glia. Here we test a number of hypotheses related to the ability of LuIII to selectively infect, replicate in, an kill human glioma. In the first set of experiments, we test the hypothesis that LuIII will successfully target and kill glioblastoma cells that are transplanted into the brain, with relativey little toxicity to the normal brain, both after an intratumoral virus injection, and after intravenus inoculation. Tumors are detected by expression of a red fluorescent reporter, and virally infected cells are detected by green immunofluorescent staining for the LuIII viral antigen NS1. A critical clinical problem with glioma is their recurrence after surgical or radiation treatment; here we tes the hypothesis that LuIII may maintain an asymptomatic low level of infection in normal human glial cells, and that LuIII arising from normal cells will thereby attenuate or block glioma cell expansion or recurrence. We will corroborate our preliminary findings and test the hypothesis that LuIII does not generate an anti-viral interferon (IFN) response, and that LuIII infection is nt attenuated by IFN. This independence from the IFN system sets LuIII apart from a number of other oncolytic viruses used in the brain which are sensitive to IFN. LuIII's insensitivity to IFN would allow a co-treatment with LuIII and IFN (IFN is a partially effective anti-tumor treatment in a subset of brain tumors), or co-treatment with LuIII together with an IFN-sensitive oncolytic virus. We will employ deep whole exome genetic sequencing, and sequencing of the mRNA transcriptome, to search for gene mutations in glioma that correlate with high levels of LuIII infection. This genetic information is useful both to understand the mechanisms underlying LuIII's selective infection of gliomas, and also may prove useful as a diagnostic predictor of which tumor-related mutations are most likely to be associated with a high LuIII infection. Finally, our preliminary data suggest that LuIII is effective at not only targeting and killing glioblastoma, but also infects and kills other cancers that invade the brain, including melanoma and lung cancer. Lung cancer metastasis is the most common problem involving secondary cancer in the brain. We will test the hypothesis that LuIII targets lung cancer cells in the brain n experiments parallel to those above involving glioma. Our central goal is to test the potential of LuIII as a safe and effective means of substantially attenuating or destroying brain tumors in humans.

描述（由申请人提供）：胶质母细胞瘤是一种侵袭性和侵袭性脑肿瘤，通常会在诊断后一年内导致死亡。目前尚无治愈方法，目前的治疗方法只能延长生命几个月，而且往往会牺牲生活质量。据报道，许多细小病毒显示出针对癌细胞的溶瘤潜力，而大鼠细小病毒 H-1 目前正在进行治疗神经胶质瘤患者的临床试验。在我们筛选大量细小病毒的最初工作中，我们发现了一种相对不起眼的细小病毒 LuIII，其表现明显优于任何其他测试的细小病毒，包括 H-1，并且是唯一一种成功杀死多个人类神经胶质瘤的细小病毒。 LuIII 在大脑中似乎是安全的，不会靶向或杀死神经元，并且对正常神经胶质细胞的感染最小。在这里，我们测试了一些与 LuIII 选择性感染、复制和杀死人类神经胶质瘤的能力相关的假设。在第一组实验中，我们测试了这样的假设：在瘤内病毒注射后和静脉内接种后，LuIII 将成功靶向并杀死移植到大脑中的胶质母细胞瘤细胞，对正常大脑的毒性相对较小。通过红色荧光报告基因的表达来检测肿瘤，通过 LuIII 病毒抗原 NS1 的绿色免疫荧光染色来检测病毒感染的细胞。神经胶质瘤的一个关键临床问题是手术或放射治疗后复发；在这里，我们测试了这样的假设：LuIII 可能在正常人神经胶质细胞中维持无症状的低水平感染，并且正常细胞产生的 LuIII 将从而减弱或阻止神经胶质瘤细胞的扩张或复发。我们将证实我们的初步发现并检验以下假设：LuIII 不会产生抗病毒干扰素 (IFN) 反应，并且 IFN 不会减弱 LuIII 感染。这种独立于 IFN 系统的特性使 LuIII 与大脑中使用的许多其他对 IFN 敏感的溶瘤病毒区分开来。 LuIII 对 IFN 不敏感，因此可以与 LuIII 和 IFN 联合治疗（IFN 是一种部分有效的抗肿瘤治疗方法）脑肿瘤的一个子集），或与 LuIII 与 IFN 敏感的溶瘤病毒共同治疗。我们将采用深度全外显子组基因测序和 mRNA 转录组测序来寻找神经胶质瘤中与高水平 LuIII 感染相关的基因突变。这种遗传信息不仅有助于理解 LuIII 选择性感染神经胶质瘤的机制，而且还可能被证明可用作诊断预测因子，预测哪些肿瘤相关突变最有可能与高 LuIII 感染相关。最后，我们的初步数据表明，LuIII 不仅能有效靶向和杀死胶质母细胞瘤，还能感染和杀死其他侵入大脑的癌症，包括黑色素瘤和肺癌。肺癌转移是涉及脑部继发性癌症的最常见问题。我们将在与上述涉及神经胶质瘤的实验平行的实验中检验 LuIII 靶向大脑中肺癌细胞的假设。我们的中心目标是测试 LuIII 作为一种安全有效的方法来显着减弱或破坏人类脑肿瘤的潜力。