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

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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.