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.

项目摘要/摘要胰腺导管腺癌（PDAC）现在是癌症相关死亡的第三主要原因美国。绝大多数患者接受全身化疗，作为新辅助的一部分，辅助治疗方案。这些系统性代理不提供持久的生存利益 PDAC患者。造成这种情况的原因是未知的，鉴于没有任何有希望的新代理商地平线，提高治疗反应或识别预防措施的新颖策略是拼命的需要。我们的小组和其他人报告了宿主微生物组对PDAC开发的重要性，进展。微生物组是微生物的环境，它们共享每个人的身体空间，越来越多地与包括胰腺癌在内的各种人类疾病有关。建立我们实验室的事先发表的工作和挑衅性的初步数据，我们提出了新的实验鉴定细菌为NK细胞的调节剂及其抗肿瘤功能，以增强对化学疗法并提供预防和治疗策略。我们利用Gnotobiotic的创新方法技术，微生物操纵和先天免疫系统，以增强PDAC的响应能力化学疗法以前尚未进行，并将推进胰腺癌研究领域。我们假设选择性肠道细菌可以延迟或防止PDAC的发展和此外，增强了吉西他滨和5-FU的常见化学治疗剂的抗肿瘤功效治疗PDAC。为了检验这一假设，我们提出以下具体目的： AIM 1：建立Hirae E. hirae的能力，以防止使用异种移植和遗传的PDAC发育胰腺癌的小鼠模型。目标2：建立Hirae对增强PDAC化学疗法功效的影响。通过实现特定目标，该提案将确认肠球菌在增强的作用 NK细胞在PDAC预防中的抗PDAC作用及其对化学疗法治疗的反应。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学疗法并提供变革性数据，以支持美国国立卫生研究院R01应用程序和用hirae进行细菌操作的首次人类试验，其针对NK细胞的抗PDAC作用预防和治疗策略。