Topic 386: Engineering probiotics to deliver chemopreventative agents to the human gut

主题 386：工程益生菌向人体肠道输送化学预防剂

• 批准号: 10020604
• 负责人: Omar Din
• 金额: $ 29.93万
• 依托单位: GENCIRQ INC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-16 至 2020-06-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020604
• 关键词: Address; Adenomatous Polyposis Coli; American; Animal Model; Apoptosis; Bacteria; Biological; Biological Assay; Blood; Cancer Etiology; Cancerous; Cessation of life; Chemoprevention; Colon; Colorectal Cancer; Communities; Consumption; Cytolysis; Engineered Probiotics; Engineering; Epidermal Growth Factor Receptor; Escherichia coli; Future; Genes; Growth; Hereditary Nonpolyposis Colorectal Neoplasms; Human; Immunocompetent; In Vitro; Inherited; Lesion; Lipoprotein Receptor; Measurement; Microfluidic Microchips; Modeling; Mus; Oral; Organ; Pathway interactions; Patients; Population; Premalignant; Prevention; Probiotics; Production; Proteins; Safety; Sampling; Small Intestines; Stomach; Syndrome; Testing; Therapeutic; Toxic effect; adenoma; cancer cell; colorectal cancer risk; design; gut colonization; high risk population; in vitro Assay; in vivo; inhibitor/antagonist; mouse model; nanobodies; prospective; receptor; screening; tumor; tumor growth

Colorectal cancer (CRC) is the second most common cause of cancer death in the US, with more than 50,000 Americans dying every year from CRC. High-risk populations that have been targeted for prevention, which include patients with inherited CRC syndromes such as familial adenomatous polyposis (FAP) and Lynch syndrome. The challenge for chemoprevention, is how to provide precision delivery and thus avoid unacceptable toxicity, in an otherwise healthy population. To address this, we propose the delivery of chemopreventative agents via a widely consumed probiotic strain of bacteria. We propose a mechanism of delivery whereby the probiotic bacteria release the chemopreventative agents via engineered lysis, by utilizing our previously established lysis paradigm for the delivery of therapeutics in vivo, where localized release increases the safety of the approach. We then anticipate that introducing pre-screened, in vitro validated engineered bacterial preventatives into a chemoprevention-directed mouse model of CRC will result in reduced local tumor growth and prolonged mouse survival in immunocompetent and human tumor mouse models, within the colon. Given that the standard 50 years and older screening population in the US can have an adenoma rate of up to 50%, there is a large opportunity to provide chemoprevention to reduce the future risk of CRC even within the general community.

结直肠癌（CRC）是美国第二大最常见的癌症死亡原因，死亡人数超过5万人