Akt3-specific Signaling Networks for Therapeutic Intervention of Triple-negative Breast Cancer

Description

Triple 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 subsetof patients. Therefore there is an unmet need to identify novel therapeutic targets forTNBC. This project is based on the premise that Akt3 is overexpressed in ~30% ofTNBC, and our recent discovery that Akt3, but not Akt1 or Akt2, is a critical regulatorfor TNBC growth. In addition, our studies have revealed a surprising finding that Akt3is implicated in acquired resistance to pan-Akt inhibitors, many of which are in clinicaltrials. These findings challenge the dogma of redundant functions of Akt isoforms intumor growth. Importantly, they point to Akt3 and its downstream substrates as noveland effective targets for breast cancer therapy.The principal goal of this research is to test the hypothesis that Akt3-specific signalingis 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 hasthree specific aims. Aim 1: We propose to identify novel Akt3-specific substrates whichregulate 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 intracellulardynamics in a real-time manner in live 3D spheroids. Aim 3: We will examine thephysiological relevance of Akt3 phosphorylation in TNBC growth and survival usingxenograft models, and evaluate the co-relation of Akt3 signaling and clinical outcomesin cancer patients. By collaborating with a team of experts in bioinformatics andmolecular profiling of breast cancer, I am confident that these proposed studies willfurther advance our understanding of Akt3 signaling in breast cancer tumorigenesis atthe molecular, cellular and in vivo levels. They will also address the unexplored role ofsubcellular localization of Akt isoforms in TNBC. Importantly, our studies will identifynovel Akt3-specific substrates that could be targeted for effective anti-cancertherapeutics.