Targeting a Kynurenine-Driven Autocrine Loop to Block Triple-Negative Breast Cancer Metastasis

靶向犬尿氨酸驱动的自分泌环来阻止三阴性乳腺癌转移

基本信息

批准号：
9229409
负责人：
Thomas J Rogers
金额：
$ 3.5万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-19 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9229409
关键词：
Affect Anoikis Apoptosis Apoptotic Aryl Hydrocarbon Receptor BCL3 gene Basement membrane Beds Binding Breast Cancer Cell Breast Cancer cell line Breast cancer metastasis Carcinoma Catabolism Cells Cellular biology Clinical Clinical Trials Complement Data Development Diagnosis Disease ERBB2 gene Endocrine Environment Enzymes Epithelium Estrogen Receptors Estrogen receptor positive Extracellular Matrix Future Gene Targeting Genes Goals Hematogenous Heterogeneity High Pressure Liquid Chromatography Image Knowledge Kynurenine Laboratories Learning Ligands Lymphatic Malignant Epithelial Cell Malignant Neoplasms Mass Spectrum Analysis Measures Mediating Mentors Metabolic Metastatic breast cancer Mission Modeling Molecular Molecular Biology Mus National Cancer Institute Neoplasm Metastasis Operative Surgical Procedures Optics Paracrine Communication Pathway interactions Patients Positioning Attribute Pre-Clinical Model Primary Neoplasm Process Production Progesterone Receptors Publishing Recurrence Relapse Research Research Personnel Research Project Grants Resistance Role Route Sampling Serum Signal Transduction Site Solid Neoplasm Suspension Culture Suspension substance Suspensions Techniques Testing Therapeutic Training Translational Research Tryptophan Tryptophanase Up-Regulation Work Xenograft procedure activating transcription factor anticancer research autocrine cancer cell cancer type career chemotherapy clinically relevant effective therapy graduate student imaging modality interest malignant breast neoplasm migration mortality neoplastic cell new therapeutic target novel novel therapeutic intervention pre-clinical student training targeted treatment triple-negative invasive breast carcinoma tumor tumor metabolism tumor microenvironment tumor progression tumorigenesis

项目摘要

Research and Related Other Project Information 7. Project Summary The subtype of breast cancer known as triple negative breast cancer (TNBC) is unresponsive to endocrine or HER2-targeted therapies. This subtype has the highest rate of recurrence and mortality in the first several years after diagnosis, but to date there are no targeted therapeutic options to treat TNBC resistant to chemotherapy. The ability of carcinoma cells to resist programmed cell death following detachment from a basement membrane or primary tumor is known as anoikis resistance, and is thought to be critical for multiple steps in the metastatic cascade. TNBC cells are more anoikis resistant than their less aggressive estrogen receptor positive (ER+) counterparts, which may explain why ER+ disease becomes metastatic less often and usually takes longer to recur. I made the novel discovery that multiple genes in the kynurenine pathway (KP) of tryptophan catabolism are upregulated in anoikis resistant, anchorage independent TNBC cells. In summary, upregulation of TDO2 in suspension promotes metastasis of TNBC via production of the intermediate tryptophan metabolite, kynurenine, and subsequent activation of AhR5. The goal of this proposal is to describe my novel graduate research and the steps to completion of my doctoral studies and how they will facilitate successful transition to a postdoctoral position, leading to an independent research position leading the field of cancer metabolism. Specifically in Aim 1, I will describe my graduate research to-date focused on the KP promoting TNBC metastasis and its important clinical implications. In Aim 2, I describe research necessary to complete my dissertation focused on further characterizing tryptophan catabolism in TNBC and downstream effectors of the KP that promote metastasis. Additionally, I explain how completion of the proposed research will facilitate transition to a competitive postdoctoral position. Aim 3 describes how I will identify a mentor under which to obtain further training in cancer metabolism during my postdoctoral studies and how to successfully transition to becoming a successful independent cancer researcher. This proposal emphasizes a molecular understanding of metabolic signaling through the kynurenine pathway that will provide the necessary preclinical framework to determine if therapeutic strategies targeting the rate limiting enzyme in this pathway, TDO2, are feasible to reduce mortality of TNBC. Furthermore, this proposal illustrates how the strengths of my graduate training in cancer cell biology and molecular biology will complement a postdoctoral position emphasizing technical training in cancer metabolism and support future translational cancer research. The completion of the proposed research will help the National Cancer Institute fulfill their mission to support cancer research leading to novel therapeutic targets and to encourage and retain enthusiastic graduate students training for a career as future independent cancer biologists.

研究和相关的其他项目信息 7。项目摘要乳腺癌的亚型称为三重阴性乳腺癌（TNBC）对内分泌或 her2靶向疗法。该亚型的复发和死亡率最高诊断后的几年，但迄今为止，没有针对性的治疗选择可以治疗TNBC的抗药性化学疗法。癌细胞抗拒编程细胞死亡后的能力地下膜或原发性肿瘤被称为厌氧抗性，被认为对多个至关重要转移级联的一步。 TNBC细胞比其侵略性较低的雌激素更具抗厌氧菌性受体阳性（ER+）对应物，这可以解释为什么ER+疾病变化较少，而通常需要更长的时间才能复发。我做出了小说的发现，即Kynurenine Pathway（KP）中的多个基因色氨酸分解代谢的抗阳性，独立的TNBC细胞上调。总之， TDO2在悬浮液中的上调通过生产中间体促进TNBC的转移色氨酸代谢产物，kynurenine和随后的AHR5激活。该建议的目的是描述我的新研究生研究以及完成博士的步骤研究以及它们将如何促进成功过渡到博士后位置，从而导致独立研究地位领导癌症代谢领域。特别是在AIM 1中，我将描述我的毕业生研究待定的重点是促进TNBC转移及其重要临床意义的KP。目标 2，我描述了完成论文所必需的研究，重点是进一步表征色氨酸促进转移的KP的TNBC和下游效应子的分解代谢。此外，我解释了如何拟议研究的完成将有助于过渡到竞争性博士后职位。目标3 描述我将如何确定一名导师在我的期间获得进一步的癌症代谢培训博士后研究以及如何成功过渡到成功的独立癌症研究员。该提议强调了通过该代谢信号的分子理解 Kynurenine途径将提供必要的临床前框架来确定是否治疗策略靶向该途径中限制酶的率TDO2是可行的，可降低TNBC的死亡率。此外，该提议说明了我在癌细胞生物学和分子生物学将补充博士后位置，强调癌症代谢的技术训练并支持未来的转化癌研究。拟议研究的完成将有助于国家癌症研究所履行了支持癌症研究的使命，导致新的治疗靶标和鼓励和保留热情的研究生作为未来独立癌症的职业培训生物学家。