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

• 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
• 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

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.

研究及其他相关项目信息 7.项目摘要 被称为三阴性乳腺癌（TNBC）的乳腺癌亚型对内分泌或免疫调节剂无反应。 HER2靶向治疗这种亚型在前几种中复发率和死亡率最高 在诊断后10年，但到目前为止，没有靶向治疗选择来治疗对TNBC耐药的TNBC。 化疗癌细胞抵抗程序性细胞死亡的能力， 基底膜或原发性肿瘤被称为失巢凋亡抵抗，并且被认为是多个肿瘤的关键。 转移级联的步骤。TNBC细胞比其不太具有侵略性的雌激素更能抵抗失巢凋亡 受体阳性（ER+）对应物，这可能解释了为什么ER+疾病转移的频率较低， 通常需要更长的时间才能复发。我有了新的发现，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，色氨酸催化剂的浓度上调。总的来说， 悬浮液中TDO 2的上调通过产生中间体促进TNBC的转移 色氨酸代谢物、犬尿氨酸和随后的AhR5活化。 这个建议的目的是描述我的小说研究生研究和步骤完成我的博士学位 研究，以及他们将如何促进成功过渡到博士后职位，导致一个独立的 在癌症代谢领域处于领先地位。在目标1中，我将描述我的毕业生 迄今为止的研究集中在KP促进TNBC转移及其重要的临床意义上。在Aim中 2，我描述了完成我的论文所需的研究，重点是进一步表征色氨酸 在TNBC中的催化剂和促进转移的KP的下游效应物。此外，我解释如何 完成拟议的研究将有助于过渡到一个有竞争力的博士后职位。目标3 描述了我将如何确定一位导师，在我的研究期间，在他的指导下，我将获得癌症代谢方面的进一步培训。 博士后研究以及如何成功过渡到成为一个成功的独立癌症 研究员该建议强调了代谢信号的分子理解，通过 犬尿氨酸途径，这将提供必要的临床前框架，以确定是否治疗策略 靶向该途径中的限速酶TDO 2对于降低TNBC的死亡率是可行的。 此外，这一建议说明了我在癌细胞生物学研究生培训的优势， 分子生物学将补充一个博士后职位，强调癌症代谢方面的技术培训 并支持未来的转化癌症研究。完成拟议的研究将有助于 美国国家癌症研究所履行其使命，支持癌症研究导致新的治疗目标， 鼓励和留住热情的研究生，为未来独立的职业生涯进行培训。 生物学家