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:
- 金额:$ 33.51万
- 依托单位:
- 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:
- 关键词:AddressAdultAnimal ModelAntiviral AgentsAntiviral ResponseAttenuatedBrainBrain NeoplasmsCell TransplantsCellsCessation of lifeClinicalClinical TrialsDataDiagnosisDiagnosticGene Expression ProfileGene MutationGenesGeneticGlioblastomaGliomaGoalsHumanInfectionInjection of therapeutic agentInterferonsInvadedLeadLifeLungMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of brainMalignant neoplasm of lungMessenger RNAMutationNeoplasm MetastasisNeurogliaNeuronsNormal CellOncolyticOncolytic virusesOperative Surgical ProceduresOutcomePTPN11 geneParvovirusPatientsPerformancePrimary Brain NeoplasmsQuality of lifeRadiationRecurrenceReporterReportingSafetySecond Primary CancersSliceSourceStaining methodStainsSystemTestingTissuesToxic effectUp-RegulationViralViral AntigensVirusVirus DiseasesWorkbasecancer celldeep sequencingexomekillingsmelanomaneoplastic celloncolysisoutcome forecastpreventpublic health relevancerat parvovirusresearch studyresponsetranscriptome sequencingtumor
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):胶质母细胞瘤是侵略性和侵入性脑肿瘤,通常在诊断后一年内导致死亡。无法治愈,目前的治疗方法仅延长了几个月,通常以牺牲生活质量为代价。据报道,许多细节性病毒表现出针对癌细胞的溶瘤潜力,而大鼠细小病毒H-1目前正在临床试验中治疗神经胶质瘤患者。在我们最初为大量细节病毒的作品中,我们发现了一个相对晦涩的细小病毒LUIII,其表现远比其他测试的其他人(包括H-1)好得多,并且是唯一成功杀死多个人类神经胶质瘤的细小病毒。 LUIII在大脑中看起来很安全,并且不靶向或杀死神经元,并且显示出正常神经胶质的最小感染。在这里,我们检验了许多与LuIII选择性感染,重复杀死人神经胶质瘤的能力有关的假设。 在第一组实验中,我们检验了以下假设:LUIII将成功地靶向和杀死被移植到大脑中的胶质母细胞瘤细胞,无论是在肿瘤内病毒注射后与正常大脑的相对毒性相对较小的毒性,并且在腔内接种后接种后。通过表达红色荧光报告剂的表达检测到肿瘤,并通过绿色免疫荧光染色检测到病毒式病毒抗原NS1的绿色免疫荧光染色。神经胶质瘤的关键临床问题是手术或放射治疗后的复发。在这里,我们提出了一个假设,即LUIII可能会在正常的人神经胶质细胞中保持无症状的低水平感染,而正常细胞引起的LUIII则会减弱或阻断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LUIII感染受到IFN的减弱。与IFN系统的这种独立性使LUIII与大脑中对IFN敏感的许多其他多种溶瘤病毒不同。 LUIII对IFN的不敏感将允许与LuIII和IFN进行共同治疗(IFN是一种部分有效的抗肿瘤治疗
脑肿瘤的子集),或与LUIII共同治疗,以及IFN敏感的溶瘤病毒。我们将采用深层外显子体遗传测序和mRNA转录组的测序来寻找与高水平的LUIII感染相关的神经胶质瘤中的基因突变。这些遗传信息对于了解LUIII的选择性感染的基础机制很有用,并且也可能被证明可作为诊断预测因子,其与肿瘤相关的突变最有可能与高LUIII感染相关。最后,我们的初步数据表明,LUIII不仅可以靶向和杀死胶质母细胞瘤,还可以感染和杀死其他侵入大脑的癌症,包括黑色素瘤和肺癌。肺癌转移是涉及大脑继发性癌症的最常见问题。我们将检验以下假设:LUIII靶向脑n实验中的肺癌细胞与上述涉及神经胶质瘤的实验。我们的核心目标是测试LUIII的潜力,是一种安全有效的手段,可以实质性地减弱或破坏人类的脑肿瘤。
项目成果
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