Evaluating Decitabine and Tazemetostat Combination Therapy in Neuroblastoma
Session Number
2
Advisor(s)
Varsha Gupta, Mark Applebaum, The University of Chicago
Location
B116
Discipline
Medical and Health Sciences
Start Date
15-4-2026 11:10 AM
End Date
15-4-2026 11:55 AM
Abstract
Neuroblastoma is the most common extracranial pediatric tumor, and high-risk MYCN-amplified disease remains difficult to treat. These tumors maintain an undifferentiated state through epigenetic repression by DNMT-mediated DNA methylation and EZH2/PRC2 activity. While tazemetostat reactivates some genes, persistent compensatory DNA methylation suggests combining it with the DNMT inhibitor decitabine may improve gene reactivation. To test this approach, MYCN-amplified neuroblastoma cell lines SK-N-BE2 and LA1-55N were treated with decitabine, tazemetostat, or their combination. The combination significantly increased neuronal differentiation compared with either single agent, indicating a shift toward a less proliferative state. To confirm on-target epigenetic effects, we examined chromatin and DNA methylation marks. Western blot analysis demonstrated reduced H3K27me3, consistent with PRC2 inhibition by tazemetostat. Dot blot analysis showed decreased global 5-methylcytosine (5mC) levels, confirming decitabine-induced DNA hypomethylation. These results suggest that combination therapy reduces histone and DNA-mediated repression, enabling activation of differentiation programs. Motif enrichment and transcriptional analyses identified CUX2 as a potential regulator. Ongoing CUX2 knockout studies aim to define its role in neuroblastoma proliferation and differentiation. Together, these findings demonstrate that dual DNMT and EZH2 inhibition reduces epigenetic repression, promotes neuronal differentiation, and highlights CUX2 as a potential downstream regulator of this response in MYCN-amplified neuroblastoma.
Evaluating Decitabine and Tazemetostat Combination Therapy in Neuroblastoma
B116
Neuroblastoma is the most common extracranial pediatric tumor, and high-risk MYCN-amplified disease remains difficult to treat. These tumors maintain an undifferentiated state through epigenetic repression by DNMT-mediated DNA methylation and EZH2/PRC2 activity. While tazemetostat reactivates some genes, persistent compensatory DNA methylation suggests combining it with the DNMT inhibitor decitabine may improve gene reactivation. To test this approach, MYCN-amplified neuroblastoma cell lines SK-N-BE2 and LA1-55N were treated with decitabine, tazemetostat, or their combination. The combination significantly increased neuronal differentiation compared with either single agent, indicating a shift toward a less proliferative state. To confirm on-target epigenetic effects, we examined chromatin and DNA methylation marks. Western blot analysis demonstrated reduced H3K27me3, consistent with PRC2 inhibition by tazemetostat. Dot blot analysis showed decreased global 5-methylcytosine (5mC) levels, confirming decitabine-induced DNA hypomethylation. These results suggest that combination therapy reduces histone and DNA-mediated repression, enabling activation of differentiation programs. Motif enrichment and transcriptional analyses identified CUX2 as a potential regulator. Ongoing CUX2 knockout studies aim to define its role in neuroblastoma proliferation and differentiation. Together, these findings demonstrate that dual DNMT and EZH2 inhibition reduces epigenetic repression, promotes neuronal differentiation, and highlights CUX2 as a potential downstream regulator of this response in MYCN-amplified neuroblastoma.