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：
10397153
负责人：
JEFF M HASTY
金额：
$ 56.85万
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/10397153
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 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 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 therapeutically effective 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.

项目概要开发有效的、具有成本效益的治疗方法来应对这一问题显然势在必行。在这里，我们通过综合开发来解决癌症给社会带来的挑战。工程细胞可有效对抗多种癌症类型，特别是结直肠癌（CRC）是癌症死亡的第二大常见原因。在美国，每年有超过 50,000 名美国人死亡。基因工程的力量在更有效的癌症治疗方面取得重大进展引入基因工程细胞，例如嵌合抗原受体T。 (CAR T) 细胞已显示出治疗多种 B 细胞恶性肿瘤的巨大前景，但是不幸的是，在这个项目中，我们将 CAR T 细胞靶向实体瘤仍然具有挑战性。使用合成生物学工具来制造基于细菌而不是基于细菌的新工程疗法某些细菌物种已表现出有用的“归巢”能力。并选择性地定植实体瘤而不感染健康组织。在拟议的工作中将利用财产直接向患者提供安全、有效的治疗最需要它们的位置：肿瘤的实心核心。细菌疗法并在转移性疾病的动物模型中进行了测试，与其他疗法相反。利用细菌细胞的方法，这种“裂解菌株”不需要专门的遗传基因对编码货物的分泌进行修改，它只是将其释放到环境中最初，我们将对裂解菌株进行基因改造，以产生多种细胞。用于测试的疗法，包括毒素（来自细菌、动物和植物）、酶、接下来我们将分析人类肿瘤微生物组。样本，因为我们认为本地细菌种群的组成将提供独特的签名（类似于指纹），可用于将肿瘤分为不同的我们希望使用这些指纹来识别其他具有卓越适用性的物种。一旦确定用于治疗 CRC 的治疗递送，我们将开发两种体外检测方法。我们将使用微流体技术来测试候选菌株。同时，我们将开发细菌和癌细胞系的共培养系统。用于从相同人类肿瘤样本中产生的细菌和类器官的系统之前已用于菌株鉴定和指纹识别，最后我们将对其进行测试。在结直肠癌动物模型中确定最有前途的疗法，以确定预治疗的疗效临床模型。