Akt3-specific Signaling Networks for Therapeutic Intervention of Triple-negative Breast Cancer
Project: Research › GRF
DescriptionTriple negative breast cancer (TNBC) is aggressive and has a poor prognosis. Currently, chemotherapy is the only treatment option but the clinical benefit is limited to a subset of patients. Therefore there is an unmet need to identify novel therapeutic targets for TNBC. This project is based on the premise that Akt3 is overexpressed in ~30% of TNBC, and our recent discovery that Akt3, but not Akt1 or Akt2, is a critical regulator for TNBC growth. In addition, our studies have revealed a surprising finding that Akt3 is implicated in acquired resistance to pan-Akt inhibitors, many of which are in clinical trials. These findings challenge the dogma of redundant functions of Akt isoforms in tumor growth. Importantly, they point to Akt3 and its downstream substrates as novel and effective targets for breast cancer therapy. The principal goal of this research is to test the hypothesis that Akt3-specific signaling is critical for TNBC growth, and to delineate the mechanisms underlying this specificity, with an emphasis on identifying new targets to treat breast cancer. This application has three specific aims. Aim 1: We propose to identify novel Akt3-specific substrates which regulate TNBC growth using a genome-wide, high-throughput proteomic screen. Aim 2: The role of subcellular localization of Akt3 in tumor spheroid growth will be examined. In particular, we will utilize CRISPR technology to tag endogenous proteins fluorescently. This would allow for the first time visualization of endogenous Akt intracellular dynamics in a real-time manner in live 3D spheroids. Aim 3: We will examine the physiological relevance of Akt3 phosphorylation in TNBC growth and survival using xenograft models, and evaluate the co-relation of Akt3 signaling and clinical outcomes in cancer patients. By collaborating with a team of experts in bioinformatics and molecular profiling of breast cancer, I am confident that these proposed studies will further advance our understanding of Akt3 signaling in breast cancer tumorigenesis at the molecular, cellular and in vivo levels. They will also address the unexplored role of subcellular localization of Akt isoforms in TNBC. Importantly, our studies will identify novel Akt3-specific substrates that could be targeted for effective anti-cancer therapeutics.
|Effective start/end date||1/01/18 → …|