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A microbiome-informed platform for the development and testing of bacterial therapies for colorectal cancer

用于开发和测试结直肠癌细菌疗法的微生物组信息平台

基本信息

批准号：
9974305
负责人：
JEFF M HASTY
金额：
$ 59.3万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2020-05-18 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9974305
关键词：
Acoustics Address American Animal Model Animal Testing Animals Antibiotics Apoptotic B lymphoid malignancy Bacteria Biological Biological Assay CRISPR/Cas technology Cancer Etiology Cancer Model Cancer cell line Cells Cessation of life Clinical Trials Cloning Coculture Techniques Colonoscopy Colorectal Colorectal Cancer Colorectal Neoplasms Consumption Cytolysis Data Development Disease Engineering Environment Enzymes Escherichia coli Evaluation Fingerprint Genetic Genetic Engineering Growth Home environment Human Human Microbiome Human body Immune response In Situ In Situ Hybridization In Vitro Lead Libraries Liquid substance Location Malignant Neoplasms Mammalian Cell Metastatic Neoplasm to the Liver Microfluidics Modeling Modification Molecular Mucous Membrane Mus Natural Products Nature Oral Organism Organoids Pathogenicity Pathologic Peptides Plants Population Population Density Pre-Clinical Model Prevalence Probiotics Property Research Sampling Series Societies Solid Solid Neoplasm System Testing Therapeutic Therapeutic Agents Therapeutic Uses Time Tissue Sample Tissues Toxin Treatment Efficacy Tumor Burden Tumor Tissue Work base beneficial microorganism cancer cell cancer therapy cancer type chemotherapy chimeric antigen receptor T cells colorectal cancer treatment cost cost effective effective therapy efficacy testing experimental study genetically modified cells human disease human tissue in vitro Assay in vivo in vivo imaging microbiome microfluidic technology mouse model novel peptide drug pre-clinical prospective synthetic biology therapeutic candidate therapeutic enzyme therapeutic evaluation therapeutic protein therapy development tool tumor tumor microbiome tumor specificity

项目摘要

Project Summary There is a clear imperative to develop potent, cost effective therapeutics to confront the challenge cancer poses to society. Here we address this need by developing synthetically engineered cells effective against a broad range of cancer types with a special emphasis on colorectal cancer (CRC). This cancer type is the second most common cause of cancer death in the US, with more than 50,000 Americans dying every year. Recent research demonstrates the power of genetic engineering to make significant advances towards more efficacious cancer therapy. The introduction of genetically engineered cells, such as chimeric antigen receptor T (CAR T) cells, has shown great promise for treating many types of B cell malignancies, but unfortunately targeting CAR T cells to solid tumors remains challenging. In this project we will use the tools of synthetic biology to make new engineered therapies based on bacterial rather than mammalian cells. Certain bacterial species have demonstrated a useful ability to “home in” and selectively colonize solid tumors without infecting healthy tissue. This tumor targeting property will be exploited in the proposed work to deliver safe, effective therapies directly to the locations where they are needed most: the solid core of tumors. Previously we developed a bacterial therapeutic and tested it in an animal model of metastatic disease. In contrast to other approaches utilizing bacterial cells, this “lysis strain” does not require specialized genetic modifications for the secretion of encoded cargo, it simply releases it into the environment when the cells burst. Initially we will genetically modify the lysis strain to produce a wide range of therapeutics for testing, including toxins (from bacteria, animals and plants), enzymes, antibiotics, and apoptotic peptides. Next we will analyze the tumor microbiome from human samples since we hypothesize that the native bacterial population's composition will provide a unique signature (analogous to a fingerprint) that can be used to divide tumors into distinct subtypes. We expect to use these fingerprints to identify other species with superior suitability for therapeutic delivery in treating CRC. Once identified we will develop two in vitro assays for testing the candidate strains. We will use microfluidic technology to create a high throughput co-culturing system for bacteria and a cancer cell line. In parallel, we will develop a co-culturing system for bacteria and organoids that are generated from the same human tumor samples which had been previously used for strain identification and fingerprinting. Lastly we will test the most promising therapies in an animal model of colorectal cancer to determine efficacy in a pre- clinical model.

项目总结