Vesicular stomatitis VSVrp30 selectively destroys human metastatic melanoma

水疱性口炎VSVrp30选择性破坏人类转移性黑色素瘤

基本信息

  • 批准号:
    8448615
  • 负责人:
  • 金额:
    $ 32.45万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-04-01 至 2017-03-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The prognosis for survival in patients with metastatic melanoma has not changed in the last 20 years and remains dismal despite advances in tumor detection and the development of melanoma-specific systemic therapies. Because of the failure of current chemotherapeutic and immunologically- based treatments to eradicate melanoma, we propose a new approach. In this proposal, we test a replication-competent oncolytic virus generated in this lab at Yale, VSVrp30. In preliminary tests VSVrp30 shows considerable promise in the potential treatment of melanoma. In vitro and in vivo experiments show that the virus selectively and rapidly infects and destroys human metastatic melanoma, with relatively little or no infection of normal human melanocytes. We seek funding to pursue experiments to determine if the virus can target and destroy melanoma cells in multiple conditions in animal and in vitro models. We will first test the oncolytic actions of the virus with a series of in vitro experiments on a large number of human melanomas and normal melanocytes available at Yale. Another set of experiments will employ human melanoma that is stably transfected with a coral reporter gene that generates a red fluorescence in the cancer cells. These human cells will be transplanted into SCID mice, both as a solid tumor, and as dispersed metastatic-like cancer cells. Virus will be given intratumorally and intravenously to test the hypothesis that the virus wll target and kill the red tumor cells with minimal infection of normal cells. Infected cells can be readily detected by the expression of a GFP reporter incorporated into the viral genome. A third set of parallel experiments will be done using the mouse melanoma line B16 in syngeneic C57Bl/6 mice with a normal immune system, allowing us to test the hypothesis that the virus can selectively detect and destroy melanoma in the presence of a normal immune system, and prolong mouse survival from melanoma; if the virus does not completely eliminate the melanoma cells, we will test the secondary hypothesis that temporarily depressing the systemic or innate immune systems with immunosuppressant drugs will enhance the oncolytic actions of the virus. A fourth set of experiments will examine the genetic mechanisms underlying the increased viral infection of melanoma cells, using an extensive series of human melanomas in which the exomes have been sequenced. These experiments will be complemented by experiments to test the hypothesis that specific induced gene mutations involving BRAF, PTEN, and CDKN2A that are common to melanoma, directly increase virus infection. A final series of experiments will test the hypothesis that the virus can cross the blood brain barrier and selectively destroy melanoma in the mouse brain, and that pre-immunization, potentially followed by transient immunosuppression, will enhance oncolysis and provide another layer of protection to the brain. If we detect collateral damage to normal brain, then we will test a new virus, 1,2-VSV, that we recently generated which is the most attenuated of any VSV we have worked with, yet still targets melanoma. Its highly attenuated nature reduces concerns relating to infection of normal brain tissue. If these experiments are successful, they will form a major advance toward clinical trials for metastatic melanoma in humans.
描述(由申请人提供):在过去的20年里,转移性黑色素瘤患者的生存预后没有改变,尽管肿瘤检测和黑色素瘤特异性全身治疗的发展取得了进展,但预后仍然令人沮丧。由于目前的化疗和基于免疫的治疗方法无法根除黑色素瘤,我们提出了一种新的方法。在本提案中,我们测试了耶鲁大学实验室生成的具有复制能力的溶瘤病毒VSVrp30。在初步测试中,VSVrp30在治疗黑色素瘤方面显示出相当大的前景。体外和体内实验表明,该病毒选择性地和迅速地感染和破坏人类转移性黑色素瘤,相对较少或不感染正常的人类黑色素细胞。我们寻求资金来进行实验,以确定病毒是否可以在动物和体外模型的多种条件下靶向和破坏黑色素瘤细胞。我们将首先在耶鲁大学大量的人类黑色素瘤和正常黑色素细胞上进行一系列的体外实验来测试病毒的溶瘤作用。另一组实验将使用人类黑色素瘤,该黑色素瘤稳定地转染了珊瑚报告基因,该基因在癌细胞中产生红色荧光。这些人类细胞将作为实体瘤和分散的转移样癌细胞移植到SCID小鼠体内。将在瘤内和静脉注射病毒,以验证病毒能在最小程度感染正常细胞的情况下靶向并杀死红色肿瘤细胞的假设。通过将GFP报告基因整合到病毒基因组中,可以很容易地检测到受感染的细胞。第三组平行实验将在具有正常免疫系统的同基因C57Bl/6小鼠中使用小鼠黑色素瘤系B16进行,使我们能够测试病毒可以在正常免疫系统存在的情况下选择性地检测和破坏黑色素瘤,并延长黑色素瘤小鼠的存活时间的假设;如果病毒不能完全消灭黑色素瘤细胞,我们将测试第二个假设,即用免疫抑制剂药物暂时抑制全身或先天免疫系统将增强病毒的溶瘤作用。第四组实验将使用一系列广泛的人类黑色素瘤,并对其外显子组进行测序,研究黑色素瘤细胞病毒感染增加的遗传机制。这些实验将辅以实验,以验证黑色素瘤常见的BRAF、PTEN和CDKN2A特异性诱导基因突变直接增加病毒感染的假设。最后的一系列实验将验证病毒可以穿过血脑屏障并选择性地破坏小鼠大脑中的黑色素瘤的假设,并且预免疫,可能随后的短暂免疫抑制,将增强肿瘤溶解并为大脑提供另一层保护。如果我们检测到对正常大脑的附带损害,那么我们将测试一种新病毒,1,2-VSV,这是我们最近产生的一种VSV,它是我们研究过的所有VSV中最弱的,但仍然针对黑色素瘤。其高度减毒的性质减少了对正常脑组织感染的担忧。如果这些实验成功,它们将在人类转移性黑色素瘤的临床试验方面取得重大进展。

项目成果

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ANTHONY N VAN DEN POL其他文献

ANTHONY N VAN DEN POL的其他文献

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{{ truncateString('ANTHONY N VAN DEN POL', 18)}}的其他基金

Zona incerta GABA neurons modulate energy homeostasis
未定带 GABA 神经元调节能量稳态
  • 批准号:
    9564671
  • 财政年份:
    2017
  • 资助金额:
    $ 32.45万
  • 项目类别:
Zona incerta GABA neurons modulate energy homeostasis
未定带 GABA 神经元调节能量稳态
  • 批准号:
    9426268
  • 财政年份:
    2017
  • 资助金额:
    $ 32.45万
  • 项目类别:
Dopamine Excites Orexigenic AgRP/NPY Neurons, but Inhibits Anorexic POMC Neurons
多巴胺兴奋促食欲 AgRP/NPY 神经元,但抑制厌食 POMC 神经元
  • 批准号:
    8888338
  • 财政年份:
    2015
  • 资助金额:
    $ 32.45万
  • 项目类别:
Lassa-VSV targets and kills glioma, and is not neurotoxic
Lassa-VSV 靶向并杀死神经胶质瘤,并且不具有神经毒性
  • 批准号:
    8888841
  • 财政年份:
    2015
  • 资助金额:
    $ 32.45万
  • 项目类别:
Dopamine Excites Orexigenic AgRP/NPY Neurons, but Inhibits Anorexic POMC Neurons
多巴胺兴奋促食欲 AgRP/NPY 神经元,但抑制厌食 POMC 神经元
  • 批准号:
    9015803
  • 财政年份:
    2015
  • 资助金额:
    $ 32.45万
  • 项目类别:
Lassa-VSV targets and kills glioma, and is not neurotoxic
Lassa-VSV 靶向并杀死神经胶质瘤,并且不具有神经毒性
  • 批准号:
    9043833
  • 财政年份:
    2015
  • 资助金额:
    $ 32.45万
  • 项目类别:
Dopamine Excites Orexigenic AgRP/NPY Neurons, but Inhibits Anorexic POMC Neurons
多巴胺兴奋促食欲 AgRP/NPY 神经元,但抑制厌食 POMC 神经元
  • 批准号:
    9213370
  • 财政年份:
    2015
  • 资助金额:
    $ 32.45万
  • 项目类别:
LuIII parvovirus targets glioma
LuIII细小病毒靶向神经胶质瘤
  • 批准号:
    8482343
  • 财政年份:
    2013
  • 资助金额:
    $ 32.45万
  • 项目类别:
LuIII parvovirus targets glioma
LuIII细小病毒靶向神经胶质瘤
  • 批准号:
    8643779
  • 财政年份:
    2013
  • 资助金额:
    $ 32.45万
  • 项目类别:
Vesicular stomatitis VSVrp30 selectively destroys human metastatic melanoma
水疱性口炎VSVrp30选择性破坏人类转移性黑色素瘤
  • 批准号:
    8826056
  • 财政年份:
    2012
  • 资助金额:
    $ 32.45万
  • 项目类别:

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