Microbiota-mediated enhancement of the anti-tumor effect of natural killer cells

微生物介导的自然杀伤细胞抗肿瘤作用的增强

基本信息

批准号：
10654555
负责人：
Christian Jobin
金额：
$ 17.47万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10654555
关键词：
Adjuvant Therapy Age Months Anatomy Antibiotics Antibodies Antitumor Response Bacteria C57BL/6 Mouse Cancer Etiology Cell physiology Cells Cessation of life Clinical Trials Colorectal Cancer Data Development Diagnosis Elements Enhancers Enterococcus Feces Fluorouracil Genetic Germ-Free Gnotobiotic Immune system Immunocompetent Immunocompromised Host In Vitro Individual Innate Immune System Integration Host Factors Interferon Type II Intestines KRASG12D Knowledge Link Malignant Neoplasms Malignant neoplasm of pancreas Mediating Mediator Modeling Mus Natural Killer Cells Neoadjuvant Therapy New Agents Oral PTEN gene Palliative Care Pancreatic Ductal Adenocarcinoma Patients Phenotype Population Prevention Prevention strategy Preventive measure Preventive treatment Production Publishing Rag1 Mouse Recurrent disease Reporting Research Role System Technology Testing Therapeutic Time Treatment Efficacy Treatment Protocols United States United States National Institutes of Health Work Xenograft Model Xenograft procedure anti-cancer anticancer research antitumor effect cancer therapy carcinogenesis chemotherapeutic agent chemotherapy experimental study first-in-human gemcitabine germ free condition gut microbiota host microbiome host microbiota human disease implantation in vivo innovation insight microbial microbiome microbiota microorganism mouse model novel novel strategies pancreatic cancer model pancreatic ductal adenocarcinoma model pancreatic tumorigenesis pathobiont patient derived xenograft model patient response personalized care prevent response screening treatment response treatment strategy tumor tumor growth

项目摘要

PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is now the 3rd leading cause of cancer related death in the United States. The overwhelming majority of patients receive systemic chemotherapy as part of a neoadjuvant, adjuvant, or palliative treatment regimen. These systemic agents do not provide durable survival benefits in patients with PDAC. The reason for this is unknown and given that there are no promising new agents on the horizon, novel strategies to increase treatment responsiveness or identify preventative measures are desperately needed. Our group and others have reported the importance of the host microbiome on PDAC development and progression. The microbiome is the milieu of microorganisms that share the body space of every individual and has been increasingly associated with a variety of human diseases, including pancreatic cancer. Building on prior published work and provocative preliminary data from our lab, we propose novel experiments that will identify bacteria as modulators of NK cells and their anti-tumor function in order to augment response to chemotherapy and provide a preventative and treatment strategy. Our innovative approach utilizing gnotobiotic technology, microbial manipulation, and the innate immune system to enhance PDAC responsiveness to chemotherapy has not been undertaken previously and will advance the field of pancreatic cancer research. We hypothesize that selective intestinal bacteria can delay or prevent PDAC development and furthermore, enhance the anti-tumor efficacy of gemcitabine and 5-FU, common chemotherapeutic agents used to treat PDAC. In order to test this hypothesis, we propose the following specific aims: Aim 1: Establish the ability of E. hirae to prevent PDAC development utilizing a xenograft and genetic mouse model of pancreatic cancer. Aim 2: Establish the impact of E. hirae to augment chemotherapy efficacy in PDAC. With fulfillment of the Specific Aims, this proposal will confirm the role of Enterococcus hirae to enhance the anti-PDAC role of NK cells in PDAC prevention as well as its response to chemotherapy treatment. Such knowledge will advance our understanding of host factors that impact the responsiveness of PDAC to chemotherapy and provide transformative data to support a National Institutes of Health R01 application and first-in-human trials for bacterial manipulation with E. hirae that targets the anti-PDAC role of NK cells as a preventative and treatment strategy.

项目概要/摘要胰腺导管腺癌 (PDAC) 目前是癌症相关死亡的第三大原因美国。绝大多数患者接受全身化疗作为新辅助治疗的一部分，辅助或姑息治疗方案。这些全身性药物不能提供持久的生存益处 PDAC 患者。其原因尚不清楚，并且考虑到目前还没有有前途的新药物地平线，提高治疗反应性或确定预防措施的新策略是迫切需要的需要。我们的小组和其他人报告了宿主微生物组对 PDAC 发育的重要性，进展。微生物组是微生物的环境，它们共享每个个体的身体空间，并且与包括胰腺癌在内的多种人类疾病的关系越来越密切。建立在之前发表的工作和来自我们实验室的具有挑战性的初步数据，我们提出了新颖的实验鉴定细菌作为 NK 细胞及其抗肿瘤功能的调节剂，以增强对化疗并提供预防和治疗策略。我们利用无菌菌的创新方法技术、微生物操作和先天免疫系统，以增强 PDAC 的反应能力以前从未进行过化疗，这将推动胰腺癌研究领域的发展。我们假设选择性肠道细菌可以延迟或阻止 PDAC 的发育，并且此外，增强常用化疗药物吉西他滨和5-FU的抗肿瘤功效治疗 PDAC。为了检验这一假设，我们提出以下具体目标：目标 1：利用异种移植物和遗传技术建立 E. hirae 阻止 PDAC 发育的能力胰腺癌小鼠模型。目标 2：确定 E. hirae 对增强 PDAC 化疗疗效的影响。随着具体目标的实现，该提案将确认海拉肠球菌在增强 NK 细胞在 PDAC 预防中的抗 PDAC 作用及其对化疗的反应。这样的知识将促进我们对影响 PDAC 响应能力的宿主因素的理解化疗并提供变革性数据以支持美国国立卫生研究院 R01 申请和首次对 E. hirae 进行细菌操作的人体试验，其目标是 NK 细胞的抗 PDAC 作用预防和治疗策略。