Signaling pathways play critical roles in executing and controlling important biological processes within cells. Cells/organisms trigger appropriate signal transduction pathways in order to turn on or off intracellular gene expression in response to environmental stimuli. An orchestrated regulation of different signaling pathways across different organs and tissues is the basis of many important biological functions. Presumably, any malfunctions or dysregulation of these signaling pathways contribute to the pathogenesis of disease, particularly cancer. In this review, we discuss how the dysregulation of signaling pathways (TGF-β signaling, Hippo signaling, Wnt signaling, Notch signaling, and PI3K-AKT signaling) modulates chromatin modifications to regulate the epigenome, thereby contributing to tumorigenesis and metastasis.
OBJECTIVES/GOALS: T develop a novel PROTAC to deplete BRK to inhibit tumorigenesis and metastasis, which is unattainable by using tradition kinase inhibitors. METHODS/STUDY POPULATION: We will design, synthesize, and evaluate BRK-specific PROTACs to study both catalytic and scaffolding properties of BRK that contribute to cancer progression. Optimal PRTOAC concentrations will be used to treat MDA-MB-231 cells to determine effects on cell proliferation, cell migration, invasion, metastatic potential, and colony formation. Immunoblotting will be used to determine target protein degradation and to evaluate if PROTAC mediated degradation of BRK allows SMAD4 to form complex with SMAD2 and SMAD3. Finally, a metastatic xenograft mouse model (MDA-MD-231) will be injected subcutaneously or via tail vein into NU/J 002019 mice8, 17 and treated with the BRK PROTAC to evaluate inhibition of tumorigenesis and metastasis. RESULTS/ANTICIPATED RESULTS: We expect that the PROTAC will specifically degrade BRK and restore the anti-tumorigenic and anti-metastatic function of SMAD4 in metastatic breast cancer. In turn, we anticipate that cell proliferation, invasion, and colony formation properties of metastatic breast cancer will be restricted and SMAD4 will form complex with SMAD2 and SMAD3. Additionally, mice treated the BRK targeted PROTAC should experience reduced tumor growth and metastasis compared to placebo. DISCUSSION/SIGNIFICANCE: This substantially new approach will inhibit oncogenic nRTKs to restore the antitumor function of TGFβ/SMAD signaling is expected to bring metastatic cancer under therapeutic control. Thus, the expected outcomes are likely to have a significant impact because it will provide a new targeted therapy to improve metastatic TNBC patient survival.
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