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

研究和其他相关项目信息 7.项目总结 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。在前几个亚型中，这个亚型的复发率和死亡率最高。 确诊数年后，但到目前为止，还没有针对性的治疗方案来治疗耐药的TNBC 化疗。癌细胞脱离细胞后抵抗细胞程序性死亡的能力 基底膜或原发肿瘤被称为失巢凋亡抵抗，被认为是多发性 在转移的级联中的步骤。与侵袭性较弱的雌激素相比，TNBC细胞对失巢凋亡的抵抗力更强 受体阳性(ER+)对应体，这可能解释了为什么ER+疾病转移较少 通常需要更长的时间才能复发。我有了一个新的发现，即犬尿氨酸途径(Kp)中的多个基因 色氨酸分解代谢的活性在失巢失巢抵抗、锚定非依赖性的TNBC细胞中上调。总而言之， 悬液中TDO2上调通过中间产物的产生促进TNBC的转移 色氨酸代谢产物犬尿氨酸，以及随后激活的AhR5。 这个提案的目的是描述我的新的研究生研究和完成我博士学位的步骤 研究以及它们将如何促进成功过渡到博士后职位，从而导致独立的 在癌症代谢领域处于领先地位。具体来说，在目标1中，我将描述我的毕业生 迄今为止的研究主要集中在KP促进TNBC转移及其重要的临床意义。在AIM 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 促进转移的TNBC和KP下游效应因子的分解代谢。此外，我还解释了如何 拟议研究的完成将有助于过渡到竞争激烈的博士后职位。目标3 描述我将如何确定一位导师，在他的指导下，在我的 博士后研究和如何成功过渡到成功的独立癌症 研究员。这一建议强调对代谢信号的分子理解，通过 犬尿氨酸途径，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TDO2可降低TNBC的死亡率。 此外，这项建议说明了我在癌症细胞生物学和研究生培训方面的优势 分子生物学将补充博士后职位，重点是癌症新陈代谢方面的技术培训 并支持未来的转化型癌症研究。拟议研究的完成将有助于 国家癌症研究所履行其使命，支持癌症研究导致新的治疗靶点和 鼓励和留住热情的研究生，为未来的独立癌症职业生涯做准备 生物学家。

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.