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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

基本信息

批准号：
9892554
负责人：
Susan Bullman
金额：
$ 24.9万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
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/9892554
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 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

项目摘要

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·布尔曼博士是马修博士实验室的多学科博士后研究员 Meyerson在Dana-Farber癌症研究所和布罗德研究所。为了配合NCI的使命，她的长期- 长期目标是领导一个独立的研究小组，研究肿瘤微生物群在肿瘤发生，发展，和治疗人胃肠道癌症，以最终降低癌症相关的死亡率和痛苦。无偏倚的基因组分析揭示了人类结直肠癌中具核梭杆菌的富集癌症（CRC）相对于非癌性结肠直肠组织的差异。外源F.动物核感染，细胞模型支持其促进癌症的作用。此外，患有高水平CRC的患者的梭杆菌在他们的肿瘤中显示出更差的存活率，这表明靶向梭杆菌可能提供一种治疗方法，新的治疗途径，增强化疗的效果，改善疾病预后。从初步数据出发，该建议将测试以下假设：（A）梭杆菌可以是作为一种新的治疗靶点用于定殖肿瘤：抑制梭杆菌属中的梭杆菌生长- 阳性患者来源的结肠直肠癌异种移植物将显著减少癌细胞增殖和肿瘤生长。生长（Aim-1），（B）F.有核菌株具有不同的促癌能力和肿瘤分析与结直肠癌中梭杆菌的定位、共存微生物群和宿主基因表达相关的生态学将鉴定预测转移的“高风险”特征（Aim-2），以及最后，（C）F. nucleatum，一个最重要的在CRC肿瘤中的丰富种类，直接调节/代谢常规癌症化疗药物，这种药物修饰有助于降低结肠癌的疗效和反应（Aim-3）。 Bullmans博士的K99阶段将在Meyerson博士的主要指导下进行：Meyerson博士是癌症基因组学，并共同发现了结直肠腺癌中梭杆菌属的富集。此外，一个由Bass博士、Dewhirst博士、Ogino博士和Schreiber博士组成的咨询委员会将对她进行监测。科学进步，职业发展，并引导她过渡到终身教职。本次培训期间将使布尔曼博士获得经验，在临床前癌症治疗模式，原位杂交方法和分析化学。在指导K99阶段，Bullman博士将专注于确定“什么梭杆菌可以做”在这些人类肿瘤，以最大限度地提高她的研究的翻译影响，并提供过渡到独立R 00阶段的基础，重点是更多的机制研究， “梭杆菌是如何做到的”布尔曼博士提出的逻辑和方法实验将提供她对梭杆菌对CRC的贡献提出了新的见解，并支持她未来的独立研究。