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

基本信息

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
项目类别：
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

项目摘要

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，肠道微生物组可能会有不足的贡献者癌症药物功效和副作用谱的个体间变化；但是，我们目前缺乏机械洞察力和来自临床前小鼠模型的数据，以告知正在进行的癌症研究患者。我们选择了包括5-氟尿嘧啶（5-FU）及其前药的Capecitabine（CAP），作为由于其在结直肠癌（CRC）疗法中的关键作用，口服给药的最初作用，因此高度可变的药代动力学以及疗效和毒性的无法解释的差异。我们提出了一系列在体外和小鼠研究中，剖析了人类肠道细菌，基因和负责的酶 5-FU的代谢（AIM 1）和CAP（AIM 2），包括对药物的下游后果药代动力学（PK）和药效学（PD）。我们的总体假设是氟吡啶胺的口服生物利用度和治疗作用受人类肠道细菌物种编码的药物代谢途径的影响。在AIM 1中，我们将确定并表征主要肠道细菌分类群，导致5-FU失活通过与gnotobiotic和异种移植研究结合的生化和基于细胞的测定的结合鼠标模型。根据我们的初步结果，我们假设Anaerostipes是主要肠道细菌属负责5-FU代谢的个体变化。在AIM 2中，我们试图发现负责激活CAP至5-FU的细菌酶令人惊讶的是，大肠杆菌可以激活帽，从而导致细菌生长降低。浓度。我们假设大肠杆菌催化了一种三步代谢途径，该途径反映了哺乳动物将盖转换为5-FU。我们在AIM 1中的结果将为剖析保护和冗余提供宝贵的原理证明在临床上相关的微生物生物转化中，有助于超越模型肠道细菌的研究确定最翻译相关的物种。 AIM 2可能是范式移动的，因为它将提供在肝细胞和癌细胞之外的帽生物活化的确切证据，创造了新的机会改善治疗结果并研究该代谢途径的生理作用和更广泛的影响。综上所述，该研究计划强调了对代谢的途径的保护跨生活领域的治疗学，强调了区分人类和微生物细胞具有药物处置，功效和副作用谱。由于我们专注于用作当前的药物护理标准和人类肠道微生物组普遍存在的天然细菌物种，这临床前研究计划具有明确的翻译相关性，并且与持续的临床相关性很高我们团队进行的癌症患者和更广泛的微生物组领域的研究。