权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Cancer-specific metabolites as cues to engineer and target anti-tumor therapeutic bacteria

癌症特异性代谢物作为设计和靶向抗肿瘤治疗细菌的线索

基本信息

批准号：
10671074
负责人：
Mohammed Dwidar
金额：
$ 22.13万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10671074
关键词：
Acidity Adhesions Area Bacteria Bacterial Adhesins Brain Breast Cancer Etiology Cancer Patient Cancer cell line Cause of Death Cell Line Cessation of life Chemotherapy and/or radiation Clinical Treatment Clinical Trials Colon Carcinoma Colorectal Colorectal Cancer Cues Diagnosis Disease Engineering Enzymes Epithelium Escherichia coli Focus Groups Foundations Funding Opportunities Future Gene Expression Gene Expression Regulation Genetic Genetic Transcription Goals Grant Head and Neck Squamous Cell Carcinoma Hypoxia Immunosuppression Kynurenine Lung Malignant Neoplasms Malignant neoplasm of cervix uteri Malignant neoplasm of lung Outcome Pathway interactions Performance Pharmaceutical Preparations Phenotype Physiological Play Probiotics Production Public Health RNA Research Resistance Role Safety Sensitivity and Specificity Site Solid Neoplasm Specific qualifier value Specificity Surface Testing Therapeutic Time Tissues Toxin Transcriptional Regulation Translations Tryptophan Work anti-cancer anti-cancer therapeutic aptamer cancer site cancer therapy cell motility experimental study improved inhibitor malignant breast neoplasm microbial microbial based therapy mouse model mouth squamous cell carcinoma neoplastic cell novel strategies protein expression response success synthetic biology targeted treatment tool tumor tumor microenvironment

项目摘要

Abstract With the ongoing advances in synthetic biology, the application of therapeutic bacteria for cancer treatment is now closer to becoming a reality. Achieving this goal, however, still needs better targeting of the therapeutic bacteria towards the cancer sites to improve the efficacy and safety of the treatment. Here, we propose to use a key cancer metabolite produced in colorectal cancers and other tumors as a cue to activate genetic circuits inside the therapeutic bacteria to control those bacteria and target them to the cancer site. To achieve this goal, we are going to clone the naturally occurring transcriptional regulator for this metabolite into engineered therapeutic E. coli and optimize its performance. In parallel, we will employ specific RNA aptamers which we already developed for this metabolite, to build synthetic riboswitches to control protein expression in the engineered Escherichia coli strain. Subsequently, these two tools; the transcription regulator, and the synthetic riboswitches, will be used in combination to build genetic circuits inside the engineered E. coli strain. These genetic circuits will then 1) Direct the engineered E. coli (along this key metabolite concentration gradient) towards the tumor site through controlling its motility, 2) Induce the attachment of this E. coli to the tumor cells, and 3) Induce the production of a therapeutic molecule within the tumor microenvironment in response to this key metabolite. During the time frame of this grant, we will be working on developing these E. coli genetic circuits which can respond to this metabolite at the physiologically relevant concentrations and we are going to test these engineered E. coli on cancer cell lines. Future work, which will be pursued through subsequent grants, will involve trying these engineered bacteria in mice models for colon cancer.

摘要随着合成生物学的不断进步，治疗性细菌在癌症治疗中的应用现在更接近成为现实。然而，要实现这一目标，仍然需要更好地靶向治疗细菌向肿瘤部位转移，以提高治疗的有效性和安全性。在这里，我们建议使用一种关键的癌症代谢物，在结直肠癌和其他肿瘤中产生，作为激活基因电路的线索在治疗性细菌中控制这些细菌，并将它们靶向癌症部位。要做到这一点 Goal，我们将把这种代谢物的天然转录调节因子克隆到工程化治疗性大肠杆菌，并优化其性能。同时，我们将使用特定的RNA 我们已经为这种代谢物开发了适配子，以构建合成核糖开关来控制蛋白质在工程菌中表达。随后，这两个工具；转录调节剂和合成核糖开关将被结合使用，在体内建立遗传电路工程化大肠杆菌菌株。然后这些遗传电路将1)引导经过改造的大肠杆菌(沿着这个键代谢物浓度梯度)通过控制其运动性向肿瘤部位移动，2)诱导这种大肠杆菌附着在肿瘤细胞上，以及3)在肿瘤细胞内诱导治疗分子的产生肿瘤微环境对这种关键代谢物的反应。在这笔赠款的时间范围内，我们将致力于开发这些大肠杆菌基因电路，它可以在生理上相关的浓度下对这种代谢物做出反应，我们将测试这些在癌细胞系上的基因工程大肠杆菌。今后的工作将通过随后的赠款进行，将包括在结肠癌的小鼠模型上试验这些工程菌。