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：
9752491
负责人：
Thomas J Rogers
金额：
$ 8.37万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9752491
关键词：
Affect Anoikis Apoptosis Apoptotic Aryl Hydrocarbon Receptor BCL3 gene Basement membrane Binding Breast Cancer Cell Breast Cancer cell line Breast cancer metastasis Carcinoma Catabolism Cell Death Cellular biology Clinical Clinical Trials Complement Data Development Diagnosis Disease ERBB2 gene Endocrine Environment Enzymes Epithelial Cells Estrogen Receptors Estrogen receptor positive Extracellular Matrix Future Genes Goals Hematogenous Heterogeneity High Pressure Liquid Chromatography In Vitro 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 Pharmacology Positioning Attribute Pre-Clinical Model Primary Neoplasm Process Production Progesterone Receptors Publishing Recurrence Relapse Research Research Personnel Research Project Grants Resistance Role Route S100A4 gene Sampling Serum Signal Transduction Site Solid Neoplasm Suspension Culture Suspensions Techniques Testing Therapeutic Training Translational Research Tryptophan Tryptophanase Up-Regulation Work Xenograft procedure anticancer research autocrine cancer cell cancer type career chemotherapy clinically relevant effective therapy graduate student imaging modality interest malignant breast neoplasm metabolic imaging migration mortality neoplastic cell new therapeutic target novel novel therapeutic intervention pre-clinical programs student training targeted treatment transcription factor translational cancer research triple-negative invasive breast carcinoma tumor tumor metabolism tumor microenvironment tumor progression tumorigenesis

项目摘要

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.

乳腺癌的亚型称为三乳腺癌（TNBC）对内分泌或靶向HER2靶向疗法无反应。该亚型在诊断后的头几年中具有最高的复发和死亡率，但是迄今为止，没有针对性的治疗选择可以治疗TNBC对化学疗法的抗性。癌细胞从地下膜或原发性肿瘤脱离后抵抗程序性细胞死亡的能力被称为厌氧性，被认为对于转移性级联反应的多个步骤至关重要。 TNBC细胞比其侵袭性较低的雌激素受体阳性（ER+）对应物更具抗厌氧菌性，这可能解释了为什么ER+疾病会降低转移性的频率较低，并且通常需要更长的时间才能复发。我发现了一个新发现，即色氨酸分解代谢的Kynurenine途径（KP）中的多个基因在耐药性，独立的独立TNBC细胞中上调。总而言之，悬浮液中TDO2的上调通过产生中间色氨酸代谢物，kynurenine和随后的AHR5激活来促进TNBC的转移。该提案的目的是描述我的新研究生研究以及完成博士研究的步骤，以及它们将如何促进过渡到博士后职位，从而导致独立的研究职位带领癌症代谢领域。特别是在AIM 1中，我将描述我的研究生研究，以促进TNBC转移的KP及其重要的临床意义。在AIM 2中，我描述了完成论文所必需的研究，重点是进一步表征TNBC和KP下游效应子的色氨酸分解代谢，从而促进转移。此外，我解释了拟议的研究的完成将如何促进过渡到竞争性博士后位置。 AIM 3描述了我将如何确定一名导师，以在我的博士后研究期间获得进一步的癌症代谢培训，以及如何成功地过渡到成为一名成功的独立癌症研究员。该提议强调了通过kynurenine途径对代谢信号传导的分子理解，该途径将提供必要的临床前框架，以确定针对该途径中限制速率酶（TDO2）的治疗策略是否可行，以降低TNBC的死亡率。此外，该建议说明了我在癌细胞生物学和分子生物学领域的研究生培训的优势如何补充博士后位置，强调癌症代谢中的技术培训并支持未来的转化癌症研究。拟议的研究的完成将有助于国家癌症研究所履行他们的任务，以支持癌症研究，从而实现新的治疗靶标，并鼓励和保留热情的研究生培训，从而成为未来独立癌症生物学家的职业。