Impact of the microbiome on chemotherapeutic outcomes

微生物组对化疗结果的影响

基本信息

批准号：
10327316
负责人：
Than Soe Kyaw
金额：
$ 4.21万
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：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10327316
关键词：
ABCB1 gene ATP-Binding Cassette Transporters Actinobacteria class Adjuvant Affect Affinity Antineoplastic Agents Binding Biochemical Biological Availability Body Weight decreased CRISPR/Cas technology California Candidate Disease Gene Cell Death Cell Line Cells Cellular Assay Chemoresistance Chemotherapy-Oncologic Procedure Colorectal Cancer Cytotoxic agent Data Dose-Limiting Doxorubicin Drug Efflux Drug Kinetics Drug toxicity Effectiveness Environment Escherichia coli Etiology Fluorescence Fluorescent Probes Foundations Fractionation Genes Genetic Polymorphism Genetic Transcription Germ-Free Gnotobiotic Goals Guide RNA Health Healthcare Heterogeneity Histology Human In Vitro Incubated Kinetics Knock-out Measures Mediating Medical Metabolism Methods Microbe Morbidity - disease rate Mus Nature Oral Outcome Patients Pharmaceutical Preparations Physicians Play Prognostic Marker Reader Rectal Cancer Rectal Neoplasms Research Research Project Grants Resistance Resources Risk Role San Francisco Scientist Serum Shapes Specificity Staging Testing Toxic effect Toxicity due to chemotherapy Training Training Programs Transcriptional Activation Transplantation Treatment outcome Universities Variant Vesicle Weights and Measures Xenograft Model anti-cancer base cancer cell cancer therapy career chemotherapeutic agent chemotherapy colon cancer cell line comorbidity comparative comparative genomics cytotoxic demographics diagnostic biomarker drug disposition drug efficacy drug response prediction experimental study gut microbes gut microbiome host microbiome imaging system improved in vitro Assay in vitro Model in vivo in vivo fluorescence imaging inhibitor insight inter-individual variation medical schools member metabolomics microbial microbial community microbiome microbiome research microbiota mortality predictive marker small molecule treatment response tumor

项目摘要

PROJECT SUMMARY/ABSTRACT Cytotoxic chemotherapeutic agents are a key component of cancer therapy, but they have unpredictable treatment responses and considerable treatment-related morbidity and mortality. Factors such as patient demographics, comorbidities, tumor types, genetic polymorphisms, and the gut microbiome may contribute to interindividual variations in chemotherapy treatment response. Of these factors, the gut microbiome is most amenable to manipulation to improve the efficacy and limit the toxicity of chemotherapy. However, the mechanisms and extent to which the microbiota affects drug disposition, and thus efficacy, remain elusive. P-glycoprotein (P-gp), a key mammalian drug efflux transporter, plays a critical role in chemotherapeutic treatment outcomes since it affects the pharmacokinetics of many cytotoxic agents and renders cancer cells resistant to anticancer drugs. Preliminary results demonstrate that the prevalent human gut Actinobacterium Eggerthella lenta inhibits P-gp function in mice, resulting in increased drug concentrations in the serum. In vitro models with human colorectal cancer (CRC) cells replicated this in vivo finding and suggested that the P-gp inhibition is mediated by a secreted bacterial metabolite. Furthermore, the P-gp inhibitor sensitized human CRC cells against a P-gp substrate anticancer drug doxorubicin. Together, these findings provide a strong scientific evidence to support the hypothesis that E. lenta secretes small molecule(s) that inhibit P-gp leading to increased drug accumulation in the tumor and improved efficacy of doxorubicin anticancer therapy. This hypothesis will be tested through 2 aims. P-gp inhibitor will be identified using comparative genomics, comparative metabolomics, and activity- guided biochemical fractionations (Aim 1a). The mechanism and the transporter specificity will be investigated with various in vitro methods (Aim 1b, 1c). The effect of E. lenta colonization on the efficacy and toxicity of doxorubicin treatment will be evaluated in a mouse rectal tumor xenograft model (Aim 2). Results from these aims will elucidate the mechanism of microbiome-transporter interactions that impacts cancer treatment outcomes. These experiments will lay a strong foundation to use the candidate genes and metabolites as prognostic biomarkers for treatment response and potential adjuvants to therapy. These research projects will be conducted at the University of California San Francisco (UCSF), which offers a unique combination of an exceptional microbiome research environment with a top-tier medical school. These research goals, in combination with a comprehensive training plan from the UCSF Medical Scientist Training Program, will be crucial to shaping the applicant's career as a physician-scientist.

项目概要/摘要细胞毒性化疗药物是癌症治疗的关键组成部分，但它们具有不可预测的作用治疗反应以及相当大的治疗相关发病率和死亡率。患者等因素人口统计学、合并症、肿瘤类型、遗传多态性和肠道微生物组可能有助于化疗反应的个体差异。在这些因素中，肠道微生物组是最重要的可以通过操作来提高化疗的疗效并限制化疗的毒性。然而，微生物群影响药物分布以及疗效的机制和程度仍然难以捉摸。 P-糖蛋白（P-gp）是一种关键的哺乳动物药物外排转运蛋白，在化疗中发挥着关键作用治疗结果，因为它影响许多细胞毒性药物的药代动力学并使癌细胞对抗癌药物有抵抗力。初步结果表明，人类肠道中普遍存在放线杆菌 Eggerthella lenta 抑制小鼠 P-gp 功能，导致血清中药物浓度增加。体外人类结直肠癌 (CRC) 细胞模型在体内复制了这一发现，并表明 P-gp 抑制作用是由分泌的细菌代谢物介导的。此外，P-gp 抑制剂使人类结直肠癌变得敏感细胞对抗 P-gp 底物抗癌药物阿霉素。总之，这些发现提供了强有力的科学依据有证据支持 E. lenta 分泌抑制 P-gp 的小分子，导致增加药物在肿瘤中的积累并提高阿霉素抗癌治疗的疗效。这个假设将是通过 2 个目标进行测试。 P-gp 抑制剂将通过比较基因组学、比较代谢组学和活性来鉴定引导生化分级分离（目标 1a）。将研究其机制和转运蛋白特异性使用各种体外方法（目标 1b、1c）。 E. lenta定植对药效和毒性的影响阿霉素治疗将在小鼠直肠肿瘤异种移植模型中进行评估（目标 2）。这些结果目标将阐明影响癌症治疗的微生物组-转运蛋白相互作用的机制结果。这些实验将为使用候选基因和代谢物作为候选基因和代谢物奠定坚实的基础。治疗反应的预后生物标志物和治疗的潜在辅助剂。这些研究项目将在加州大学旧金山分校 (UCSF) 进行，提供卓越的微生物组研究环境与顶级医学院的独特组合。这些研究目标与加州大学旧金山分校医学科学家的全面培训计划相结合培训计划对于塑造申请人作为医师科学家的职业生涯至关重要。