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：
10526594
负责人：
Mohammed Dwidar
金额：
$ 18.82万
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/10526594
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 Coculture Techniques Colon Carcinoma Colorectal Colorectal Cancer Cues Diagnosis Disease Engineering Enzymes Epithelial 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 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 base cancer site cancer therapy cell motility experimental study improved inhibitor malignant breast neoplasm microbial mouse model mouth squamous cell carcinoma neoplastic cell novel strategies probiotic therapy 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.

抽象的随着合成生物学的持续进展，治疗细菌在癌症治疗中的应用是现在更接近成为现实。但是，实现这一目标仍然需要更好地靶向治疗性向癌症部位的细菌提高治疗的功效和安全性。在这里，我们建议使用在结直肠癌和其他肿瘤中产生的关键癌症代谢物作为激活遗传回路的提示在治疗细菌内部控制这些细菌并将其靶向癌症部位。实现这一目标目标，我们将克隆此代谢物的自然发生的转录调节剂设计了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产物开发的适体，以构建合成核糖开关以控制蛋白质在工程大肠杆菌菌株中的表达。随后，这两个工具；转录调节剂和合成核糖开关将组合使用，以建立遗传回路设计的大肠杆菌菌株。这些遗传回路将1）指导工程的大肠杆菌（沿此钥匙代谢物浓度梯度）通过控制其运动性，朝向肿瘤部位，2）诱导该大肠杆菌附着在肿瘤细胞上，3）在肿瘤细胞中诱导治疗分子的产生肿瘤微环境响应这种关键代谢产物。在这笔赠款的时间范围内，我们将努力开发这些大肠杆菌遗传回路在生理上相关的浓度下对这种代谢产物做出反应，我们将测试这些代谢物在癌细胞系上设计了大肠杆菌。未来的工作将通过随后的赠款进行，将涉及在结肠癌的小鼠模型中尝试这些工程细菌。