Genetic Improvements of Tumor-Targeted Salmonella

针对肿瘤的沙门氏菌的遗传改良

基本信息

  • 批准号:
    6548941
  • 负责人:
  • 金额:
    $ 10万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2002
  • 资助国家:
    美国
  • 起止时间:
    2002-08-09 至 2003-01-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Salmonella are under development as anticancer vectors. In mice, attenuated Salmonella injected intravenously or intratumorally multiply preferentially within tumors, suppress tumor growth and prolong survival. One strain, VNP20009, is currently in human Phase I clinical trials. A key mutation in VNP20009, a partial deletion of the msbB gene which renders the bacterial endotoxin virtually incapable of eliciting septic shock, also makes the bacteria sensitive to a variety of salt and chelating agents, generally limiting the growth of the bacteria under certain conditions. Spontaneously arising strains with compensatory mutations were previously isolated which included VNP20009, and their antitumor activity determined. Growth properties of these strains were partially restored, but their efficacy ranged from little or no antitumor activity in one strain, to those such as VNP20009 with a high degree of antitumor activity. Thus, these compensatory mutations are both diverse and important for efficacy of antitumor strains. Recently, by applying alternate selection techniques and a broader spectrum of physiological assays, a much wider diversity of spontaneous compensatory mutations which restore resistance to part or all of these sensitivities were isolated. Thus, because the broad spectrum of compensatory mutations was only recently recognized, only a few of these have been tested for antitumor activity thus far. Here, we propose to isolate this broad spectrum of compensatory mutants using transposon mutagenesis and to move these insertions into tumor-selective strains, thereby generating new antitumor strains with the potential for improved properties. These new strains of Salmonella with compensatory mutations will be tested for antitumor activity. PROPOSED COMMERCIAL APPLICATIONS: Highly selectie bacterial vectors working directly at diseased sites throughout the body offer the potential to eradicate diseased tissue with substantially reduced side effects due to non-specific toxicity. We anticipate that patients with untreatable and inaccessible metastatic and solid tumors will be the primary markets. The first Salmonella vector, VNP20009, is already in human phase I clinical trials for treatment of solid tumors.
描述(由申请人提供):沙门氏菌正在开发作为抗癌载体。在小鼠中,静脉注射或瘤内注射的减毒沙门氏菌优先在肿瘤内繁殖,抑制肿瘤生长并延长生存期。其中一个菌株 VNP20009 目前正在进行人体 I 期临床试验。 VNP20009中的一个关键突变,即msbB基因的部分缺失,使得细菌内毒素几乎无法引发感染性休克,也使细菌对多种盐和螯合剂敏感,通常会限制细菌在某些条件下的生长。先前分离出具有补偿突变的自发菌株,其中包括 VNP20009,并测定了它们的抗肿瘤活性。这些菌株的生长特性得到了部分恢复,但其功效范围从一种菌株几乎没有或没有抗肿瘤活性,到诸如VNP20009等具有高度抗肿瘤活性的菌株。因此,这些补偿性突变是多种多样的,并且对于抗肿瘤菌株的功效很重要。最近,通过应用替代选择技术和更广泛的生理测定,分离出更广泛多样性的自发补偿突变,这些突变恢复了对部分或全部这些敏感性的抵抗力。因此,由于广泛的补偿性突变最近才被认识到,因此迄今为止仅测试了其中少数的抗肿瘤活性。在这里,我们建议使用转座子诱变分离这种广泛的补偿突变体,并将这些插入转移到肿瘤选择性菌株中,从而产生具有改善特性潜力的新抗肿瘤菌株。这些具有补偿性突变的沙门氏菌新菌株将接受抗肿瘤活性测试。 拟议的商业应用: 直接作用于全身患病部位的高度选择性细菌载体提供了根除患病组织的潜力,同时大大减少了由于非特异性毒性而产生的副作用。我们预计患有无法治疗和难以接近的转移性实体瘤患者将成为主要市场。第一个沙门氏菌载体 VNP20009 已进入治疗实体瘤的人体 I 期临床试验。

项目成果

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DAVID G BERMUDES其他文献

DAVID G BERMUDES的其他文献

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{{ truncateString('DAVID G BERMUDES', 18)}}的其他基金

California State University - Interdisciplinary Cancer Meeting (CSU-ICM)
加州州立大学 - 跨学科癌症会议 (CSU-ICM)
  • 批准号:
    10066294
  • 财政年份:
    2020
  • 资助金额:
    $ 10万
  • 项目类别:
Tumor-targeting Salmonella expressing apoptosis-inducing cytotoxic proteins
表达细胞凋亡诱导细胞毒性蛋白的肿瘤靶向沙门氏菌
  • 批准号:
    8414763
  • 财政年份:
    2013
  • 资助金额:
    $ 10万
  • 项目类别:
Tumor-targeting Salmonella expressing apoptosis-inducing cytotoxic proteins
表达细胞凋亡诱导细胞毒性蛋白的肿瘤靶向沙门氏菌
  • 批准号:
    8660303
  • 财政年份:
    2013
  • 资助金额:
    $ 10万
  • 项目类别:
Tumor-targeting Salmonella expressing apoptosis-inducing cytotoxic proteins
表达细胞凋亡诱导细胞毒性蛋白的肿瘤靶向沙门氏菌
  • 批准号:
    9026621
  • 财政年份:
    2013
  • 资助金额:
    $ 10万
  • 项目类别:
Tumor-targeting Salmonella expressing apoptosis-inducing cytotoxic proteins
表达细胞凋亡诱导细胞毒性蛋白的肿瘤靶向沙门氏菌
  • 批准号:
    8827374
  • 财政年份:
    2013
  • 资助金额:
    $ 10万
  • 项目类别:
TUMOR-TARGETING SALMONELLA EXPRESSING TUMOR-SELECTIVE CYTOTOXIC PROTEINS IN COMBINATION WITH PROTEASE INHIBITORS
表达肿瘤选择性细胞毒性蛋白的肿瘤靶向沙门氏菌与蛋白酶抑制剂的组合
  • 批准号:
    10321211
  • 财政年份:
    2013
  • 资助金额:
    $ 10万
  • 项目类别:
SALMONELLA WITH INDUCIBLE ANTICANCER GENES
具有诱导抗癌基因的沙门氏菌
  • 批准号:
    6074570
  • 财政年份:
    2000
  • 资助金额:
    $ 10万
  • 项目类别:
REDUCED TOXICITY OF TUMOR-TARGETED SALMONELLA
降低针对肿瘤的沙门氏菌的毒性
  • 批准号:
    2728391
  • 财政年份:
    1998
  • 资助金额:
    $ 10万
  • 项目类别:

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