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.

被称为三阴性乳腺癌 (TNBC) 的乳腺癌亚型对内分泌或 HER2 靶向治疗没有反应。这种亚型在诊断后的最初几年内复发率和死亡率最高，但迄今为止，还没有针对化疗耐药的 TNBC 的靶向治疗方案。癌细胞在从基底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失巢凋亡抵抗，并且被认为对于转移级联中的多个步骤至关重要。 TNBC 细胞比侵袭性较低的雌激素受体阳性 (ER+) 细胞更能抵抗失巢凋亡，这可能解释了为什么 ER+ 疾病不易发生转移且通常需要更长的时间才能复发。我的新发现是，色氨酸分解代谢的犬尿氨酸途径 (KP) 中的多个基因在抗失巢凋亡、不依赖贴壁的 TNBC 细胞中上调。总之，悬浮液中 TDO2 的上调通过产生中间色氨酸代谢物犬尿氨酸以及随后激活 AhR5 来促进 TNBC 的转移。该提案的目的是描述我新颖的研究生研究和完成博士研究的步骤，以及它们将如何促进成功过渡到博士后职位，从而获得领导癌症代谢领域的独立研究职位。具体来说，在目标 1 中，我将描述我迄今为止的研究生研究，重点是 KP 促进 TNBC 转移及其重要的临床意义。在目标 2 中，我描述了完成论文所需的研究，重点是进一步表征 TNBC 中的色氨酸分解代谢和促进转移的 KP 下游效应器。此外，我还解释了完成拟议的研究将如何促进向有竞争力的博士后职位的过渡。目标 3 描述了我将如何找到一位导师，在我的博士后研究期间获得癌症代谢方面的进一步培训，以及如何成功过渡成为一名成功的独立癌症研究员。该提案强调对犬尿氨酸途径代谢信号的分子理解，这将提供必要的临床前框架，以确定针对该途径中的限速酶 TDO2 的治疗策略是否可以降低 TNBC 的死亡率。此外，该提案还说明了我在癌细胞生物学和分子生物学方面的研究生培训的优势将如何补充强调癌症代谢技术培训的博士后职位，并支持未来的转化癌症研究。拟议研究的完成将帮助国家癌症研究所履行其使命，支持癌症研究以实现新的治疗目标，并鼓励和留住热情的研究生，为未来的独立癌症生物学家的职业生涯进行培训。