Genetic Improvements of Tumor-Targeted Salmonella

针对肿瘤的沙门氏菌的遗传改良

• 批准号: 6548941
• 负责人: DAVID G BERMUDES
• 金额: $ 10万
• 依托单位: VION PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/6548941
• 关键词: Salmonella typhimurium; antineoplastics; attenuated microorganism; biotechnology; gene delivery system; gene mutation; gene targeting; gene therapy; laboratory mouse; neoplasm /cancer genetics; neoplasm /cancer pharmacology

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）：沙门氏菌作为抗癌媒介正在开发中。在小鼠中，静脉或肿瘤内注射的沙门氏菌在肿瘤中优先繁殖，抑制肿瘤的生长并延长生存率。一种菌株VNP20009目前正在人类I期临床试验中。 VNP20009中的一个关键突变是MSBB基因的部分缺失，它几乎无法引起败血性休克的细菌内毒素，这也使细菌对各种盐和螯合剂敏感，通常在某些条件下限制细菌的生长。先前将带有代偿突变的菌株自发产生，其中包括VNP20009，并确定其抗肿瘤活性。这些菌株的生长特性得到了部分恢复，但其功效范围从一个菌株中的抗肿瘤活性很少或没有抗肿瘤活性到具有高度抗肿瘤活性的VNP20009。因此，这些补偿性突变对于抗肿瘤菌株的疗效既多样化又重要。最近，通过应用替代选择技术和更广泛的生理测定范围，可以分离出对部分或所有这些敏感性的耐药性的自发补偿突变的多样性。因此，由于最近才识别出广泛的补偿性突变，因此迄今为止仅测试了其中的一些抗肿瘤活性。在这里，我们建议使用转座子诱变分离出这种广泛的补偿性突变体，并将这些插入将其移动到肿瘤选择性菌株中，从而产生新的抗肿瘤菌株，从而有可能改善特性。这些新的带有补偿性突变的沙门氏菌菌株将用于抗肿瘤活性。 拟议的商业应用： 高度选择的细菌向量直接在整个体内的患病部位工作，这为消除患病组织的潜力大大降低了，由于非特异性毒性而降低了副作用。我们预计患有不可治疗且无法接近转移性和实体瘤的患者将成为主要市场。第一个沙门氏菌载体VNP20009已经在人类I期临床试验中，用于治疗实体瘤。