Engineering S. typhimurium for metastatic colorectal cancer

工程鼠伤寒沙门氏菌治疗转移性结直肠癌

基本信息

批准号：
9973552
负责人：
Tal Danino
金额：
$ 34.67万
依托单位：
COLUMBIA UNIV NEW YORK MORNINGSIDE
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：
2020-06-15 至 2024-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9973552
关键词：
3-Dimensional Animal Model Animals Antitumor Response Attenuated Automobile Driving Bacteria Biological Assay CD47 gene CD8B1 gene Cancer Biology Cancer Model Cell Death Cell Line Cells Clinical Clinical Trials Coculture Techniques Colorectal Colorectal Cancer Combined Modality Therapy Communities Cues Cytolysis Databases Development Diagnostic Disease Engineering Environment Euthanasia Evaluation Fluorescence Microscopy Future Genes Genetic Genetic Engineering Genetic Programming Goals Growth Heterogeneity Histologic Home environment Homing Human Human body Hypoxia Immunologic Surveillance Immunotherapeutic agent Infiltration Intelligence Libraries Liver Malignant Neoplasms Metastatic Neoplasm to the Liver Microbe Microscopy Modeling Molecular Mus Necrosis Neoplasm Metastasis Oral Organ Pathogenicity Peptides Performance Population Prevalence Production Reporter Research Route Safety Salmonella typhimurium Solid Neoplasm Source Specificity System Testing Therapeutic Time Toxic effect Toxin Treatment Efficacy Tumor Tissue anti-cancer anti-cancer therapeutic attenuation base cancer therapy cell type clinical translation colorectal cancer treatment cytotoxicity draining lymph node effective therapy effector T cell efficacy study immunogenicity improved in vivo imaging system interest lead candidate metastatic colorectal microbiome research mouse model novel novel therapeutics preclinical toxicity response safety study safety testing screening spatiotemporal synergism synthetic biology therapeutic evaluation therapy outcome time use tool tumor tumor growth tumor hypoxia tumor microenvironment vector

项目摘要

The engineering of living cells and microbes is driving a new era of cancer therapy. This transformative approach allows for the genetic programming of living cells to intelligently sense and respond to environments, ultimately adding specificity and efficacy that is otherwise unattainable with molecular-based therapeutics. Due to recent microbiome studies indicating the prevalence of bacteria within the human body and specifically in tumor tissue, bacteria have generated significant interest as cancer therapies. Additionally, a multitude of empirical studies have demonstrated that administered bacteria home and selectively grow in tumors due to reduced immune surveillance of tumor cores. Given their presence and selectivity for tumors, bacteria present a unique oppor- tunity to be engineered as intelligent delivery vehicles for cancer therapy. The objective of this proposal is to engineer and optimize S. typhimurium for metastatic colorectal cancer therapy. Since animal based-testing regimes limit the rate of clinical progress, we will use a high-throughput, bacteria-spheroid platform to rapidly test therapeutic payloads and production and release strategies. We will also assess the effect of therapies on colorectal genetic backgrounds, and investigate spatio-temporal hetero- geneity in 3D spheroids with the use of engineered cell reporters. We will then test lead candidates in mouse models of primary and metastatic colorectal cancer to evaluate safety and efficacy. We will focus on colorectal cancer due to several proof-of-concept studies from our lab demonstrating efficacy in colorectal spheroids and animal models. In particular, we showed that oral delivery of bacteria can specifically colonize colorectal liver metastases, providing an attractive delivery route as a cancer therapy. Since these metastases are often con- fined to the liver, this approach can have a significant impact on tumor growth and survival. The research in this proposal will help to establish a framework to genetically engineer microbes for cancer therapy, and significantly accelerates tools that will impact the broader cancer and synthetic biology communities. If successful, future lead candidates for potential clinical trials will be identified on the basis of therapeutic efficacy and safety studies from this proposal.

活细胞和微生物的工程正在推动癌症治疗的新时代。这种变革性的方法允许活细胞的遗传编程智能地感知并响应环境，最终添加基于分子的治疗剂否则无法实现的特异性和功效。由于最近微生物组的研究表明人体内，特别是在肿瘤组织中的流行率，细菌作为癌症疗法引起了巨大的兴趣。另外，许多经验研究已经证明，由于免疫降低，施用的细菌家园并有选择地在肿瘤中生长肿瘤核心的监视。鉴于它们对肿瘤的存在和选择性，细菌具有独特的oppor- 将其设计为用于癌症治疗的智能送货车。该建议的目的是设计和优化鼠伤寒沙门氏菌的转移性结直肠癌治疗。由于基于动物的测试机制限制了临床进度的速度，因此我们将使用高通量，细菌 - 球形平台可快速测试治疗有效载荷以及生产和释放策略。我们将还要评估疗法对结直肠遗传背景的影响，并研究使用工程细胞记者使用3D球体中的基因。然后，我们将在鼠标中测试铅候选者原发性和转移性结直肠癌的模型，以评估安全性和有效性。我们将专注于大肠癌症是由于我们实验室的几项概念证明研究，证明了结直肠球体和动物模型。特别是，我们表明细菌的口服递送可以特异性地定居结直肠肝转移，提供有吸引力的输送途径作为癌症疗法。由于这些转移通常是这种方法被罚款，可以对肿瘤生长和生存产生重大影响。这项研究提案将有助于建立一个遗传学工程师微生物进行癌症治疗的框架，并显着加速会影响更广泛的癌症和合成生物学社区的工具。如果成功，未来将根据治疗功效和安全性研究确定潜在临床试验的主要候选者从这个建议。