A multicentric translational clinical study on the role of the oro-intestinal microbiome in pancreatic cancer chemotherapy

关于口腔肠道微生物组在胰腺癌化疗中作用的多中心转化临床研究

• 批准号: 513977356
• 负责人: Professor Dr. Christoph Karl Stein-Thöringer
• 金额: --
• 依托单位: Innere Medizin I: Gastroenterologie, Hepatologie, Infektionskrankheiten
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/513977356?language=en
• 关键词: multicentric; translational; clinical; study; role

Pancreatic ductal adenocarcinoma (PDAC) is a frequent cancer type, but with a miserable prognosis of a 5-year overall survival of only 9%. Most patients present with advanced stage disease and require systemic therapies with chemotherapy. Current poly-chemotherapeutic regimens can improve overall survival, but are associated with considerable side effects and toxicity, often preventing their application in elderly patients and/or patients with poor performance status. As biomarkers that can predict treatment efficacy against PDAC are currently lacking, we cannot reliably stratify patients in those who will benefit vs. those that will largely suffer from toxicity. In recent years, the gut microbiome has been identified to predict and modulate the efficacy of anticancer immunotherapies. Currently, little is known about its role in chemotherapy-based systemic treatments in solid tumors. Therefore, there is large unmet medical need on biomarkers predicting critical outcomes of chemotherapy in PDAC patients, and to investigate whether microbiome features are associated with it in order to develop mechanistic hypotheses on microbe-cancer-therapy interactions and on druggable targets for future therapeutic interventions. In the present research proposal, we aim to perform microbiome metagenome sequencing from a multicentric German cohort of locally advanced and metastatic PDAC patients receiving standard-of-care chemotherapies. Since 2020, we are prospectively recruiting patients (N = 131) and collecting serial saliva and stool biospecimens after diagnosis until 6 months of systemic therapy. Here, we will study longitudinal changes of the oral and fecal microbiome over the course of therapy and investigate associations of microbiome features – species, genes and metabolic pathways – with therapy response, survival and development of toxicities as major clinical outcomes in a final cohort of 200 patients and 800 microbiome samples in total. Utilizing shotgun metagenome sequencing, we will also generate an unprecedented data set on how chemotherapeutic agents modify the gene reservoir of the gut microbiome which may have drastic effects on gut microbial homeostasis and microbe-host interactions. Finally, applying machine-learning driven prediction models, we will explore microbiome-based classifiers and will include clinical features and molecular tumor characteristics herein with the overall goal to propose a biomarker for therapy outcomes in PDAC patients.

胰腺导管腺癌 (PDAC) 是一种常见的癌症类型，但预后很差，5 年总生存率仅为 9%。大多数患者出现晚期疾病，需要化疗等全身治疗。目前的多种化疗方案可以提高总体生存率，但与相当大的副作用和毒性相关，通常阻碍其在老年患者和/或体力状态不佳的患者中的应用。由于目前缺乏可以预测 PDAC 治疗效果的生物标志物，因此我们无法可靠地将患者分为受益者和严重中毒者。近年来，肠道微生物组已被确定可以预测和调节抗癌免疫疗法的疗效。目前，人们对其在实体瘤化疗全身治疗中的作用知之甚少。因此，对于预测 PDAC 患者化疗关键结果的生物标志物以及研究微生物组特征是否与其相关，以便制定关于微生物-癌症-治疗相互作用的机制假设以及未来治疗干预的药物靶标，存在大量未满足的医疗需求。在本研究提案中，我们的目标是对接受标准护理化疗的德国多中心局部晚期和转移性 PDAC 患者队列进行微生物组宏基因组测序。自 2020 年起，我们前瞻性地招募患者 (N = 131)，并在诊断后收集连续唾液和粪便生物样本，直至接受 6 个月的全身治疗。在这里，我们将研究治疗过程中口腔和粪便微生物组的纵向变化，并研究微生物组特征（物种、基因和代谢途径）与治疗反应、生存和毒性发展的关联，作为最终队列的 200 名患者和总共 800 个微生物组样本的主要临床结果。利用鸟枪法宏基因组测序，我们还将生成前所未有的数据集，了解化疗药物如何改变肠道微生物组的基因库，这可能对肠道微生物稳态和微生物-宿主相互作用产生巨大影响。最后，应用机器学习驱动的预测模型，我们将探索基于微生物组的分类器，并将临床特征和分子肿瘤特征纳入本文，总体目标是为 PDAC 患者的治疗结果提出生物标志物。