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

基本信息

批准号：
10321211
负责人：
DAVID G BERMUDES
金额：
$ 10.88万
依托单位：
CALIFORNIA STATE UNIVERSITY NORTHRIDGE
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：
2013-05-10 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10321211
关键词：
Animals Antineoplastic Agents Apoptosis Attenuated Bacteria Biodistribution Breast Cancer Model Cancer Model Cancerous Chimera organism Clinical Research Clinical Trials Data Development Disease Distant Dose Drug Delivery Systems Effectiveness Engineering Epidermal Growth Factor Receptor Funding Generations Goals Human In Vitro Individual Intravenous Lead Malignant Neoplasms Metalloproteases Modeling Mus Pathogenicity Patients Peptide Hydrolases Process Protease Inhibitor Proteins Proteolysis Pseudomonas aeruginosa toxA protein Research Safety Salmonella Site Solid Neoplasm Sunflowers Targeted Toxins Testing Therapeutic Agents Time Tissues Toxic effect Toxin Trypsin Inhibitors Xenograft procedure aggressive breast cancer anti-cancer anticancer activity antitumor effect attenuation base cancer cell cancer therapy cytotoxic design human model improved in vivo inhibitor matriptase mouse model mutant neoplastic cell optical imaging prevent protein degradation therapeutic protein translational study triple-negative invasive breast carcinoma tumor tumor xenograft vector whole body imaging

项目摘要

PROJECT SUMMARY/ABSTRACT Tumor-targeting bacteria offer a number of advantages over other cancer drug delivery systems, including targeting of multiple tumors from a distant inoculation site, selective intratumoral replication, a high degree of attenuation and safety, and the ability to express anti-cancer proteins directly within the tumor. Remarkably, attenuated Salmonella localize within solid tumors at levels at least 1000 times greater than other tissues. Human clinical studies have validated the safety of intravenously administered attenuated Salmonella mutant VNP20009, established tolerated multiple doses, and have shown that tumor targeting occurs in some patients. However, no anti-tumor activity was observed, even in patients in whom the Salmonella were verified to have colonized their tumors. We hypothesize that the lack of antitumor efficacy in the human clinical trials can be overcome by engineering antitumor apoptosis (programmed cell death) -inducing cytotoxic proteins that are able to selectively kill tumor cells, and that the ability of these proteins to kill cancer cells can be enhanced by blocking their degradation by tumor proteases through co-expression of protease inhibitors. The specific aims are designed to test the tumor-selective toxin generated during the initial SC3 funding period in murine models of cancer. The specific aims are also directed toward generation and analysis of individual protease inhibitor combinations expressed by VNP20009 in order to prevent proteolytic degradation of the therapeutic protein and develop tumor-targeted Salmonella vectors with enhanced antitumor activity. VNP20009 expressing a tumor-cell targeted toxin will be analyzed alone and in combination with one or more protease inhibitors using optical imaging of the bacterial interaction with murine tumor models of highly aggressive breast cancer. The results are expected to indicate the effectiveness of the targeted toxin and the effect(s) of the protease inhibitors alone and in combination with the toxin. These results have the potential to improve VNP20009 without increasing its toxicity, and therefore could lead to translational studies in humans. .

项目概要/摘要与其他癌症药物输送系统相比，肿瘤靶向细菌具有许多优势，包括从远处接种位点靶向多个肿瘤、选择性肿瘤内复制、高度的减毒和安全性，以及直接在细胞内表达抗癌蛋白的能力瘤。值得注意的是，减毒沙门氏菌以至少 1000 倍的水平定位于实体瘤内大于其他组织。人体临床研究验证了静脉注射的安全性给予减毒沙门氏菌突变体 VNP20009，建立了耐受的多次剂量，并已表明肿瘤靶向发生在一些患者身上。然而，没有观察到抗肿瘤活性，即使在经证实沙门氏菌已在肿瘤中定植的患者中也是如此。我们假设人体临床试验中抗肿瘤功效的缺乏可以通过抗肿瘤工程来克服细胞凋亡（程序性细胞死亡）-诱导能够选择性杀死肿瘤的细胞毒性蛋白细胞，并且这些蛋白质杀死癌细胞的能力可以通过阻断它们来增强通过蛋白酶抑制剂的共表达被肿瘤蛋白酶降解。具体目标是旨在测试 SC3 初始资助期间在小鼠体内产生的肿瘤选择性毒素癌症模型。具体目标还针对个人的生成和分析 VNP20009 表达的蛋白酶抑制剂组合，以防止蛋白水解降解治疗蛋白并开发具有增强抗肿瘤作用的肿瘤靶向沙门氏菌载体活动。表达肿瘤细胞靶向毒素的 VNP20009 将单独和组合分析与一种或多种蛋白酶抑制剂一起使用细菌与鼠肿瘤相互作用的光学成像高度侵袭性乳腺癌模型。预计结果将表明该方法的有效性靶向毒素以及蛋白酶抑制剂单独和与毒素组合的作用。这些结果有可能在不增加毒性的情况下改进 VNP20009，因此可能会导致人类的转化研究。。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（1）

EGFR-targeted Chimeras of Pseudomonas ToxA released into the extracellular milieu by attenuated Salmonella selectively kill tumor cells.

DOI：
10.1002/bit.26026
发表时间：
2016-12
期刊：
BIOTECHNOLOGY AND BIOENGINEERING
影响因子：
3.8
作者：
Quintero, David;Carrafa, Jamie;Vincent, Lena;Bermudes, David
通讯作者：
Bermudes, David

A culture-based method for determining the production of secreted protease inhibitors.

一种基于培养的方法，用于确定分泌型蛋白酶抑制剂的产生。

DOI：
10.1016/j.mimet.2014.02.019
发表时间：
2014
期刊：
Journal of microbiological methods
影响因子：
2.2
作者：
Quintero,David;Bermudes,David
通讯作者：
Bermudes,David

Co-Expression of a Chimeric Protease Inhibitor Secreted by a Tumor-Targeted Salmonella Protects Therapeutic Proteins from Proteolytic Degradation.

靶向肿瘤沙门氏菌分泌的嵌合蛋白酶抑制剂的共表达可保护治疗性蛋白质免遭蛋白水解降解。

DOI：
10.4014/jmb.1807.08036
发表时间：
2018
期刊：
Journal of microbiology and biotechnology
影响因子：
2.8
作者：
Quintero,David;Carrafa,Jamie;Vincent,Lena;Lee,HeeJong;Wohlschlegel,James;Bermudes,David
通讯作者：
Bermudes,David

Accumulation of single-stranded DNA in Escherichia coli carrying the colicin plasmid pColE3-CA38.