Metabolism of cancer chemotherapeutics by the human gut microbiome

人类肠道微生物组对癌症化疗药物的代谢

• 批准号: 10635361
• 负责人: Peter James Turnbaugh
• 金额: $ 60.32万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10635361
• 关键词: Accounting; Affect; Analytical Chemistry; Animal Model; Antimetabolites; Antineoplastic Agents; Bacteria; Bacterial Genes; Biochemical; Biological Assay; Biological Availability; Caenorhabditis elegans; Cancer Etiology; Cancer Model; Cancer Patient; Cells; Cessation of life; Circulation; Clinical; Clinical Research; Colorectal Cancer; Coupled; Data; Dihydropyrimidine Dehydrogenase; Drug Kinetics; Drug resistance; Drug usage; Enzymes; Escherichia coli; Fluorouracil; Future; Genes; Genetic; Genotype; Gnotobiotic; Growth; Hepatocyte; Homologous Gene; Human; Human Microbiome; Immunotherapy; Impairment; In Vitro; Interdisciplinary Study; Intestines; Life; Malignant Neoplasms; Metabolic Biotransformation; Metabolic Pathway; Metabolism; Methods; Mus; Mutagenesis; Operon; Oral; Oral Administration; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiological; Positioning Attribute; Prevalence; Prodrugs; Research; Role; Series; Source; Study models; Taxon; Testing; Therapeutic; Therapeutic Effect; Toxic effect; Treatment outcome; Vertebral column; Work; Xenograft Model; Xenograft procedure; bacterial genetics; bacterial resistance; cancer cell; cancer therapy; capecitabine; carcinogenesis; clinically relevant; colon cancer patients; colorectal cancer treatment; design; dietary supplements; drug disposition; drug efficacy; drug metabolism; evidence base; experience; experimental study; fluoropyrimidine; gut bacteria; gut microbes; gut microbiome; gut microbiota; improved; in vivo; individual variation; individualized medicine; insight; inter-individual variation; metastatic colorectal; microbial; microbiome; mouse model; pharmacokinetics and pharmacodynamics; pharmacologic; pre-clinical; pre-clinical research; pressure; programs; pyrimidine metabolism; response; side effect; standard of care; tool; tumor metabolism

PROJECT SUMMARY Rigorous data from our lab and others indicate that the gut microbiome may an underappreciated contributor to inter-individual variations in cancer drug efficacy and side effect profiles; however, we currently lack the mechanistic insights and data from preclinical mouse models necessary to inform ongoing studies in cancer patients. We selected fluoropyrimidines, including 5-fluorouracil (5-FU) and its prodrug capecitabine (CAP), as an initial test case due to their critical role in colorectal cancer (CRC) therapy, increasing oral administration, highly variable pharmacokinetics, and unexplained differences in efficacy and toxicity. We propose a series of in vitro and mouse studies to dissect the human gut bacterial species, genes, and enzymes responsible for the metabolism of 5-FU (Aim 1) and CAP (Aim 2), including their downstream consequences for drug pharmacokinetics (PK) and pharmacodynamics (PD). Our overarching hypothesis is that the oral bioavailability and therapeutic effects of fluoropyrimidines are influenced by pathways for drug metabolism encoded by diverse human gut bacterial species. In Aim 1, we will identify and characterize the primary gut bacterial taxon responsible for 5-FU inactivation through a combination of biochemical and cell-based assays coupled to studies in gnotobiotic and xenograft mouse models. Based on our Preliminary Results, we hypothesize that Anaerostipes is the primary gut bacterial genus responsible for inter-individual variations in the metabolism of 5-FU. In Aim 2, we seek to discover the bacterial enzymes responsible for the activation of CAP to 5-FU, motivated by the surprising finding that E. coli can activate CAP leading to reduced bacterial growth at high concentrations. We hypothesize that E. coli catalyzes a 3-step metabolic pathway that mirrors the mammalian conversion of CAP to 5-FU. Our results in Aim 1 will provide a valuable proof-of-principle for dissecting the conservation and redundancies in clinically relevant microbial biotransformations, helping to move beyond studies of model gut bacteria to identify the most translationally relevant species. Aim 2 is potentially paradigm-shifting in that it would provide definitive evidence for CAP bioactivation outside of hepatocytes and cancer cells, creating new opportunities to improve treatment outcomes and study the physiological role and broader impacts of this metabolic pathway. Taken together, this research plan emphasizes the conservation of the pathways for metabolism of therapeutics across domains of life, highlighting the need to distinguish the relative contributions of human and microbial cells to drug disposition, efficacy, and side effect profiles. Due to our focus on drugs used as current standard of care and naturally occurring bacterial species prevalent in the human gut microbiome, this preclinical research program has clear translational relevance and is highly synergistic with ongoing clinical studies of cancer patients conducted by our team and the broader microbiome field.

项目摘要 来自我们实验室和其他实验室的严格数据表明，肠道微生物组可能是一个未被充分认识的贡献者， 癌症药物疗效和副作用特征的个体间差异;然而，我们目前缺乏 为正在进行的癌症研究提供信息所必需的临床前小鼠模型的机制见解和数据 患者我们选择了氟嘧啶类药物，包括5-氟尿嘧啶（5-FU）及其前药卡培他滨（CAP）， 由于它们在结肠直肠癌（CRC）治疗中的关键作用，增加口服给药， 高度可变的药代动力学，以及无法解释的疗效和毒性差异。我们提出了一系列 体外和小鼠研究，以解剖人类肠道细菌物种，基因和酶，负责 5-FU（目的1）和CAP（目的2）的代谢，包括其对药物的下游影响 药代动力学（PK）和药效学（PD）。 我们的总体假设是，氟嘧啶的口服生物利用度和治疗效果 受多种人类肠道细菌编码的药物代谢途径的影响。 在目标1中，我们将鉴定和表征负责5-FU失活的主要肠道细菌分类群 通过结合生物化学和基于细胞的分析，以及对非生物和异种移植物的研究， 小鼠模型。根据我们的初步结果，我们假设Anaerostipes是主要的肠道 导致5-FU代谢个体间变异的细菌属。 在目的2中，我们试图发现负责CAP活化为5-FU的细菌酶， 令人惊讶的发现，E.大肠杆菌可以激活CAP，导致细菌生长在高 浓度的我们假设E.大肠杆菌催化一个三步代谢途径， CAP转化为5-FU。 我们在目标1中的结果将为剖析守恒和冗余提供有价值的原理证明 在临床相关的微生物生物转化，帮助超越模型肠道细菌的研究， 找出最重要的物种目标2可能会改变范式，因为它将提供 CAP在肝细胞和癌细胞外生物活化的明确证据，为 改善治疗结果，研究这一代谢途径的生理作用和更广泛的影响。 总之，这项研究计划强调保护代谢途径， 跨生命领域的治疗，强调需要区分人类和 微生物细胞对药物处置、功效和副作用概况的影响。由于我们专注于当前使用的药物， 标准的护理和人类肠道微生物组中普遍存在的天然存在的细菌物种， 临床前研究计划具有明确的转化相关性，并与正在进行的临床研究高度协同 我们的团队对癌症患者进行的研究以及更广泛的微生物组领域。