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

• 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
• 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

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.

项目摘要 明确的必须开发潜力，具有成本效益的疗法来对抗 挑战癌症对社会构成构成。在这里我们通过合成来满足这种需求 工程细胞有效地抵抗广泛的癌症类型，特别强调 结直肠癌（CRC）。这种癌症类型是癌症死亡的第二大原因 在美国，每年有50,000多名美国人死亡。最近的研究表明 基因工程的力量，取得更大效率的癌症的重大进步 治疗。引入一般设计的细胞，例如嵌合抗原受体T （CAR T）细胞，显示了治疗多种B细胞恶性肿瘤的巨大前景，但 不幸的是，将汽车T细胞靶向实体瘤仍然受到挑战。在这个项目中，我们将 使用合成生物学的工具来制作基于细菌的新工程疗法 比哺乳动物细胞。某些细菌物种表现出“回家”的有用能力 并选择性地定居实体瘤而不感染健康组织。这个肿瘤靶向 将在拟议的工作中探讨财产，以直接将安全有效的疗法提供给 最需要的位置：肿瘤的实心核心。以前我们开发了 细菌治疗并在转移性疾病的动物模型中对其进行了测试。与其他 使用细菌细胞的方法，这种“裂解应变”不需要专门的通用 对编码货物的分泌进行修改，它只是将其释放到环境中时 细胞破裂。最初，我们将通常修改裂解应变，以产生广泛的范围 用于测试的治疗，包括毒素（来自细菌，动物和植物），酶， 抗生素和凋亡肽。接下来，我们将分析人类的肿瘤微生物组 样本由于我们假设本地细菌种群的成分将提供 独特的签名（类似于指纹），可用于将肿瘤分为不同 亚型。我们希望使用这些指纹识别具有出色适合性的其他物种 用于治疗CRC的治疗分娩。一旦确定，我们将开发两个体外测定 测试候选菌株。我们将使用微流体技术来创建高通量 细菌和癌细胞系的共培养系统。同时，我们将共同培养 从相同的人类肿瘤样品产生的细菌和器官的系统 以前用于应变识别和指纹。最后我们将测试 在结直肠癌的动物模型中，最有前途的疗法确定效率 临床模型。