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

被称为三阴性乳腺癌(TNBC)的乳腺癌亚型对内分泌或HER2靶向治疗无效。这种亚型在确诊后的头几年中复发率和死亡率最高，但到目前为止还没有针对性的治疗方案来治疗化疗耐药的TNBC。癌细胞从基底膜或原发肿瘤脱落后抵抗程序性细胞死亡的能力被称为失巢凋亡抵抗，被认为在转移级联反应的多个步骤中起关键作用。与不太具侵袭性的雌激素受体阳性(ER+)细胞相比，TNBC细胞对失巢凋亡的抵抗力更强，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，色氨酸分解代谢的犬尿氨酸途径(KP)中的多个基因在失巢耐药、锚定非依赖性的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和随后激活AhR5来促进TNBC的转移。 这项建议的目标是描述我的新的研究生研究和完成我的博士研究的步骤，以及它们将如何促进我成功地过渡到博士后职位，从而获得一个领导癌症新陈代谢领域的独立研究职位。具体地说，在目标1中，我将描述我到目前为止的研究生研究，重点是KP促进TNBC转移及其重要的临床意义。在目标2中，我描述了完成我的论文所必需的研究，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下游效应因子。此外，我还解释了拟议研究的完成将如何促进向具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，在我博士后学习期间在他的指导下获得关于癌症新陈代谢的进一步培训，以及如何成功地过渡到成为一名成功的独立癌症研究人员。这一建议强调通过犬尿氨酸途径对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的治疗策略是否可行，以降低TNBC的死亡率。此外，这项提议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我的博士后职位，强调癌症代谢方面的技术培训，并支持未来的癌症转化性研究。这项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目标，并鼓励和留住热情的研究生，为未来独立的癌症生物学家的职业生涯做准备。

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.