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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和响应环境，增加了分子疗法无法达到的特异性和功效。由于最近微生物组研究表明细菌在人体内特别是在肿瘤组织中的流行，细菌作为癌症疗法已经引起了极大的兴趣。此外，大量的实证研究已经证明，由于免疫功能降低，施用的细菌在肿瘤中归巢并选择性生长，监测肿瘤核心。鉴于它们的存在和对肿瘤的选择性，细菌呈现出独特的机会， tunity将被设计成癌症治疗的智能运载工具。本文的目的是设计和优化S。鼠伤寒沙门氏菌治疗转移性结直肠癌疗法由于基于动物的测试制度限制了临床进展的速度，我们将使用高通量，细菌球体平台，以快速测试治疗有效载荷和生产和释放策略。我们将还评估了治疗对结直肠遗传背景的影响，并研究了时空异质性。使用工程化细胞报告基因的3D球状体。然后，我们将在小鼠中测试主要候选人原发性和转移性结直肠癌模型，以评估安全性和有效性。我们将重点关注结直肠由于我们实验室的几项概念验证研究证明了在结直肠球体中的疗效，动物模型特别是，我们发现口服细菌可以特异性地定植在结肠直肠肝脏转移，提供作为癌症治疗的有吸引力的递送途径。由于这些转移瘤往往是并发的-- 这种方法可以对肿瘤的生长和存活产生重大影响。这项研究该提案将有助于建立一个框架，以基因工程微生物用于癌症治疗，加速将影响更广泛的癌症和合成生物学社区的工具。如果成功，未来将在疗效和安全性研究的基础上确定潜在临床试验的主要候选药物从这个提议。