COMBINATIONAL THERAPY FOR MELANOMA USING ZEBULARINE AS AN EPIGENETIC INHIBITOR AND TOLL-LIKE RECEPTOR AGONISTS AS IMMUNOTHERAPY

Date

2025-8

Author

Homak, Havva

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Oncotherapy faces significant obstacles due to the complex nature of cancer. Notably, therapy-induced or tumor-mediated immunosuppression and cancer recurrence after remission remain substantial challenges. Emerging modalities such as immunotherapy, which augments the cytotoxic activity of immune cells, and epigenetic therapy, which aims to reprogram the genome of malignant cells toward a non-cancerous state, have been developed to address these concerns. However, monotherapies often show limited efficacy in overcoming all these hurdles. This study therefore aims to investigate the potential benefits of combining immunotherapy and epigenetic therapy for melanoma treatment. To achieve this, we screened nine Food and Drug Administration (FDA) approved epigenetic inhibitors for their immunostimulatory properties to identify candidates suitable for combination with a cancer vaccine comprising nucleic acid-based Toll-like receptor (TLR) agonists and ovalbumin as a model antigen. Our findings indicate that zebularine, a DNA methyltransferase (DNMT) inhibitor, when used alongside CpG oligodeoxynucleotides (ODN), a TLR9 agonist, enhances immune responses in murine splenocytes and increases cytotoxicity against B16 melanoma cells. In addition, this combination therapy reduces tumor growth and induces antigen-specific adaptive immune responses in an in vivo melanoma mouse model. In summary, zebularine augments the immune responses elicited by CpG ODN, and their combined administration represents a promising strategy for reprogramming tumor cells and improving therapeutic outcomes.

Subject Keywords

Immunotherapy, Epigenetic therapy, CpG ODN, Zebularine, Melanoma

URI

https://hdl.handle.net/11511/115640

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Graduate School of Natural and Applied Sciences, Thesis