Pancreatic cancer (PC) is extremely lethal. Early metastasis prior to diagnosis, tumor recurrence and resistance towards current chemo-radiation therapies are common among PC patients. Recent evidence indicates that the acquisition of epithelial-to-mesenchymal transition (EMT) and induction of cancer stem cell (CSC) phenotypes in PC tumors are important underlying causes for these occurrences. However, the mechanisms leading to EMT and CSC phenotypes remain unclear. This information is critical for the discovery of novel targeted therapies for the treatment of PC that offer superior outcome. The long term goal is to identify therapeutically effective drug targets in PC. Our recent unpublished data have uncovered a critical role of Aurora A (AA) kinase in promoting EMT and CSC in PC. AA is upregulated in PC and contributes significantly to tumorigenesis and metastasis;however, the molecular mechanisms remain unknown. Using an innovative chemical genetic screen, FOXM1 transcription factor was identified as a direct target of AA in highly malignant AsPC1 cells. AA directly phosphorylates FOXM1 at S361 stabilizing its levels. In turn, FOXM1 also stabilizes AA levels, thereby triggering a reciprocal positive feedback loop. FOXM1 upregulation is known to promote EMT and CSC phenotypes in PC cells. The objective in this proposal is to determine the contribution of FOXM1 as a critical effector of AA by which it promotes EMT and CSC phenotype in PC tumors. The central hypothesis is that AA and FOXM1 are potential drug targets which promote aggressive oncogenic pathways in PC synergistically. This hypothesis will be tested by pursuing three specific aims: 1) Determine a potential role of AA in promoting EMT and CSC in PC cells. 2) Determine the consequences of AA-mediated phosphorylation of FOXM1 on various oncogenic pathways in PC cells. 3) Determine AA and FOXM1 levels in tandem in human clinical samples and their correlation with clinical outcomes. The approach is innovative because the central hypothesis was formulated based on a novel AA substrate, FOXM1, discovered using a powerful chemical genetic approach. No cancer-specific substrate of AA has been identified in PC. AA has not been linked to CSC or EMT to date. Furthermore, FOXM1 or AA levels have not been analyzed in tandem in human PC tissues. The proposed research is significant because validation of FOXM1 as an AA substrate will provide a potent tool to inhibit FOXM1 deregulation in metastatic PC. Correlation of AA and FOXM1 levels with divergent clinical outcomes are expected to reveal potential prognostic and diagnostic biomarkers for PC. The positive impact of our work will be the validation of AA as a potential drug target for treating/preventing EMT, CSC and chemoresistance, either alone or in combination with FOXM1 inhibitors.
The proposed studies with an enzyme Aurora A (AA) will aid in the development of more effective therapy for metastatic pancreatic cancer (PC). Analysis of AA and FOXM1 levels in human clinical samples should aid in the development of novel prognostic and diagnostic biomarkers for PC progression and help the oncologists in disease management decisions.
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