The role of Fusobacterium in colorectal cancer treatment, tumor ecology and chemotherapeutic efficacy

梭杆菌在结直肠癌治疗、肿瘤生态学和化疗疗效中的作用

• 批准号: 9982913
• 负责人: Susan Bullman
• 金额: $ 22.03万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982913
• 关键词: Address; Advisory Committees; Affect; Analytical Chemistry; Animal Model; Bacteria; Bass; Biology; Cancer Etiology; Cancer Model; Cell Proliferation; Cell model; Cessation of life; Chemicals; Chemotherapy-Oncologic Procedure; Colon Carcinoma; Colonic Neoplasms; Colorectal; Colorectal Adenocarcinoma; Colorectal Cancer; Colorectal Neoplasms; Dana-Farber Cancer Institute; Data; Development; Disease; Early Diagnosis; Ecology; Faculty; Fluorescent in Situ Hybridization; Foundations; Fusobacterium; Fusobacterium nucleatum; Future; Gene Expression; Gene Expression Profile; Genomics; Goals; Growth; Growth Inhibitors; Human; Immunotherapy; In Situ Hybridization; In Vitro; Infection; Institutes; Laboratories; Lead; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Mentors; Mentorship; Methods; Microbe; Microbial Biofilms; Mission; Modeling; Modification; Molecular; Molecular Profiling; Monitor; Neoplasm Metastasis; Pathology; Pathway interactions; Patients; Phase; Positioning Attribute; Prediction of Response to Therapy; Recurrence; Research; Risk; Role; Route; Testing; Tissues; Training; United States; Validation; Virulent; Woman; Xenograft procedure; cancer cell; cancer diagnosis; cancer genomics; cancer therapy; carcinogenicity; career; career development; chemotherapy; cohort; colorectal cancer treatment; community organizations; drug efficacy; drug modification; effective therapy; experience; experimental study; genome analysis; high risk; high risk population; improved; in vivo; inhibitor/antagonist; insight; member; men; metastatic colorectal; microbial genomics; microbial host; microbiome; microbiota; mortality; multidisciplinary; neoplastic cell; new therapeutic target; novel; novel therapeutics; outcome forecast; patient subsets; pre-clinical; predictive marker; predictive signature; response; small molecule; stem; targeted treatment; tenure track; transcriptome; translational impact; tumor; tumor growth; tumor microbiota

PROJECT SUMMARY Dr. Susan Bullman is a multi-disciplinary postdoctoral research fellow in the laboratory of Dr. Matthew Meyerson at the Dana-Farber Cancer Institute and Broad Institute. In alignment with the NCI mission, her long- term goal is to lead an independent research group studying the role of tumor microbiota in initiation, progression, and treatment of human gastrointestinal cancers to ultimately reduce cancer-associated mortality and suffering. Unbiased genomic analyses have revealed an enrichment of Fusobacterium nucleatum, in human colorectal cancers (CRC) relative to non-cancerous colorectal tissues. Exogenous F. nucleatum infection in animal and cellular models has supported its cancer-promoting role. Additionally, patients with CRC that harbor high levels of Fusobacterium in their tumors show worse survival, suggesting that targeting Fusobacterium may provide a novel therapeutic route, potentiate the effects of chemotherapies, and improve disease prognosis. Stemming from preliminary data, this proposal will test the hypotheses that (A) Fusobacterium can be used as a novel therapeutic target in colonized tumors: inhibition of Fusobacterium growth in Fusobacterium- positive patient derived colorectal cancer xenografts will significantly reduce cancer cell proliferation and tumor growth (Aim-1), (B) F. nucleatum strains have varying pro-carcinogenic capabilities and analysis of tumor ecology relating to Fusobacterium’s localization, co-occurring microbiota, and host gene expression in CRC will identify “high-risk” signatures predictive of metastasis (Aim-2), and finally, (C) F. nucleatum, one of the most abundant species in CRC tumors, directly modulates/metabolizes routine cancer chemotherapeutics and that this drug modification contributes to diminished efficacy and response in colon cancers (Aim-3). Dr. Bullmans K99 phase will be performed under the primary mentorship of Dr. Meyerson: a leader in cancer genomics and co-discovered the enrichment of Fusobacterium in colorectal adenocarcinomas. Additionally, an advisory committee consisting of Drs. Bass, Dewhirst, Ogino and Schreiber will monitor her scientific progress, career development, and guide her transition to a tenure-track faculty position. This training period will allow Dr. Bullman to gain experience in pre-clinical cancer treatment models, in-situ hybridization approaches, and analytical chemistry. In the mentored K99 phase Dr. Bullman will focus on determining “what Fusobacterium can do” in these human tumors, to maximize the translational impact of her research and provide the foundation for transition to the independent R00 phase, with a focus on more mechanistic studies addressing “how Fusobacterium is doing it”. The logical and methodical experiments proposed by Dr. Bullman will provide novel insights into the contribution of Fusobacterium to CRC and support her future independent research.

项目摘要 苏珊·布尔曼（Susan Bullman）博士是马修博士实验室的多学科博士后研究员 Dana-Farber癌症研究所和Broad Institute的Meyerson。为了与NCI任务保持一致，她的长期 术语目标是领导一个独立的研究小组，研究肿瘤微生物群在起始，进展中的作用， 并治疗人类胃肠道癌，最终降低与癌症相关的死亡率和痛苦。 公正的基因组分析表明，在人类结直肠癌中富集了核细菌的核细菌 癌症（CRC）相对于非癌直肠组织。动物和 细胞模型支持其癌症促进作用。此外，具有高水平的CRC患者 其肿瘤中的梭杆菌的生存率较差，表明靶向镰刀菌可能会提供 新型热路线，潜在的化学疗法影响并改善疾病进展。 由于初步数据，该提案将检验（a）镰刀杆菌的假设 用作定植肿瘤中的新型热靶标：抑制叶杆菌的梭杆菌生长 阳性患者衍生的结直肠癌Xenographictics将显着减少癌细胞的增殖和肿瘤 生长（AIM-1），（b）F。核菌株具有不同的促癌能力和肿瘤的分析 与梭菌的定位，同时存在的微生物群和宿主基因表达有关的生态学将 确定可预测转移（AIM-2）的“高风险”特征，最后，（c）F。nucleatum，其中之一是最多的。 CRC肿瘤中的大量物种，直接调节/代谢常规癌症治疗疗法，并将其代谢 这种药物修饰会导致结肠癌的效率和反应降低（AIM-3）。 Bullmans K99阶段博士将在Meyerson博士的主要心态下进行： 癌症基因组学并共同发现了结直肠腺癌中梭杆菌的富集。 此外，由DRS组成的咨询委员会。低音，Dewhirst，Ogino和Schreiber将监视她 科学进步，职业发展，并指导她过渡到终身教师职位。这个培训 期间将使Bullman博士获得临床前癌症治疗模型的经验，现场杂交 方法和分析化学。在修订的K99阶段，Bullman博士将专注于确定“什么 在这些人类肿瘤中，梭菌可以做到”，以最大化她的研究的翻译影响并提供 过渡到独立R00阶段的基础，重点是针对更多机械研究 “镰刀杆菌的做法”。 Bullman博士提出的逻辑和有条理的实验将提供 新颖的见解对Fusobacterium对CRC的贡献并支持她未来的独立研究。