dUTPase inhibitors have recently emerged as a novel class of cancer therapeutic designed to work alongside thymidylate synthase (TS) inhibitors to significantly improve efficacy and patient outcome.
When dUTPase inhibitors (DUTi) are used in combination with TS inhibitors, there is a significant increase in DNA damage and enhanced cancer cell lethality. One novel and exciting aspect of this synergistic drug combination is the concurrent stimulation of cancer innate immune signaling. The first project Aim is designed to identify the molecular causation for the stimulation of this immune signaling with DUTi, and determine if this phenomenon be exploited in combinations with immune checkpoint inhibitors. DUTi can also significantly enhance the anticancer activity of anthracyclines, another class of widelyprescribed cancer therapeutics employed in difficult-to-treat cancers like triple-negative breast cancer.
The mechanism for this synergistic interaction is unknown and at the hypothesis stage. The second Aim will seek to identify the molecular mechanisms by which DUTi significantly enhance the anticancer activity of anthracyclines and explore the potential for future clinical evaluation of combining DUTi with anthracyclines. This project employs a blend of conventional and cutting edge pre-clinical in vitro and in vivo molecular biology techniques to address these fundamentally important questions.
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