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Engineering tumor-targeting bacteria to sense and deliver therapeutics

工程化肿瘤靶向细菌来感知和提供治疗

基本信息

批准号：
10654915
负责人：
Tetsuhiro Harimoto
金额：
$ 8.58万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-10 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10654915
关键词：
3-Dimensional Address Animal Model Antibiotics Attenuated Bacteria Bacterial Genes Bacteriophages Biosensor CT26 Cancer Model Cell Death Cells Chemoresistance Coculture Techniques Colon Colorectal Colorectal Cancer Colorectal Neoplasms Complex Computer Models Coupled Development Disease Progression Dose Engineered Gene Engineering Environment Feedback Fusobacterium nucleatum Genes Goals Growth Homing Human body Hypoxia Immunologic Surveillance In Situ In Vitro Intelligence Libraries Malignant Neoplasms Mammalian Cell Methods Microbe Microscopy Modeling Monitor Mus Necrosis Oncogenic Organism Oxygen Patients Peptides Phase Plasmids Population Prevalence Production Rapid screening Research Research Project Grants Research Proposals Risk Role Salmonella typhimurium Solid Neoplasm Specificity System Technology Testing Therapeutic Therapeutic Agents Time Tissues Toxic effect Treatment Efficacy Tropism Tumor Tissue Work base cancer cell cancer therapy clinical candidate clinical translation colorectal cancer progression colorectal cancer treatment commensal microbes cytotoxic delivery vehicle dynamic system effective therapy gut microbes gut microbiota improved in vivo microbial microbiome research microbiota mouse model next generation novel novel strategies pathogen programs response sensor skills spatiotemporal synthetic biology therapeutic candidate therapy outcome tool tumor tumor hypoxia tumor microbiota tumor microenvironment tumor progression

项目摘要

Project Summary The ability to engineer living cells as intelligent therapeutic agents is poised to transform current cancer treatment paradigms. Based on the inherent growth specificity of some natural and exogenous bacteria to solid tumors, microbes have been explored as programmed vehicles to deliver therapeutics to tumor environments. However, a universal challenge for developing this next-generation living therapy is the lack of tools to study the dynami- cally interacting population of bacteria and cancer cells. Consequently, the vast majority of the past studies have relied on animal models that only test a handful of therapeutic candidates and provide limited spatiotemporal information. To address this challenge, I have recently developed a 3D multicellular coculture platform that ena- bles high-throughput characterization of bacteria in tumor spheroids, assessing dynamics of multicellular inter- actions and predicting therapeutic efficacy in vivo. In this proposal, I will leverage the 3D coculture technologies and synthetic biology tools to construct novel bacterial systems that sense and express therapeutics specifically in tumors. In the F99 phase, I will engineer tumor-homing bacteria to dynamically regulate production of cytotoxic molecules in response to tumor shrinkage. Specifically, as the cancer cell death increases the level of oxygen in the tumor core, I will engineer a bacterial biosensor circuit to monitor this change in the tumor microenvironment. By detecting rises in oxygen levels, which indicate extensive therapeutic progression, this gene circuit will reduce the therapeutic level produced, minimizing off-target toxicity. In the K00 phase, I will repurpose tumor-homing bacteria to target and eradicate oncogenic F. nucleatum in colorectal cancer. I will apply the 3D coculture platform to screen anti-F. nucleatum peptides delivered by bacteria to tumor spheroids. Orthotropic mouse cancer models will be used to assess the F. nucleatum elimination, effect on commensal microbiota, and cancer progression. Collectively, the proposed work will utilize a novel engineering framework to develop effective bacterial cancer therapies towards clinical translation.

项目总结