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: 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
• 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

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。 癌症给社会带来的挑战。在这里，我们通过综合开发来满足这一需求 工程细胞可有效对抗多种癌症类型，特别是 结直肠癌（CRC）。这种癌症类型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。最近的研究表明 基因工程的力量在更有效的癌症治疗方面取得重大进展 治疗。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，将 CAR T 细胞靶向实体瘤仍然具有挑战性。在这个项目中我们将 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 比哺乳动物细胞。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。这种肿瘤靶向 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。之前我们开发了一个 细菌疗法并在转移性疾病的动物模型中进行了测试。与其他相比 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 细胞破裂了。最初，我们将对裂解菌株进行基因改造，以产生多种 用于测试的疗法，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肿瘤微生物组 样本，因为我们假设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 亚型。我们希望利用这些指纹来识别其他具有卓越适用性的物种 用于治疗 CRC 的治疗递送。一旦确定，我们将开发两种体外检测方法 测试候选菌株。我们将利用微流控技术来创造高通量 细菌和癌细胞系的共培养系统。与此同时，我们将开发一个共培养 用于从相同人类肿瘤样本中产生的细菌和类器官的系统 以前曾用于菌株鉴定和指纹识别。最后我们将测试 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。