Abstract B022: Targeting Neuroblastoma Persister Cells with Menin Inhibition Combined with Chemotherapy
Abhishek Wahi, Emily A. Cmarik, Jennifer E. Sturgis, Nathaniel W. MabeAbstract
Background:
Neuroblastoma is the most common extracranial pediatric cancer and accounts for approximately 15% of childhood cancer-related deaths. Despite dose-intensive, multimodal treatment, nearly half of patients will relapse with no treatments available and is nearly always fatal. It is likely that a small subset of residual tumor cells that persist after intensive chemotherapy, called drug-tolerant persister (DTP) cells, seed relapsed tumors by adopting reversible epigenetic states that confer tolerance to stress. Thus, elimination of these residual cells is required to reduce relapse in high-risk neuroblastoma patients.
Results:
To identify genes required for DTP formation, we performed parallel in vivo and in vitro CRISPR screens of epigenetic modulators in neuroblastoma cells treated with irinotecan, a chemotherapy use for relapsed/refractory neuroblastoma. Our screens identified that genetic knockout of either MEN1 (encoding menin) or KMT2A (encoding MLL1) sensitized neuroblastoma cells to irinotecan, which we confirmed in competition and viability assays. Considering the recent interest and FDA-approval of menin inhibitors in pediatric leukemias, we tested whether revumenib or ziftomenib impact neuroblastoma growth in the presence of several chemotherapies. We found that ziftomenib more strongly synergized with several chemotherapies as compared to revumenib, perhaps due to more strongly reducing menin[NWM1] expression with ziftomenib treatment. Notably, combination treatment reduced viability strongest around day 10 when DTPs emerge. Using an inducible H2B-GFP system to isolate DTPs, we identified that persistence manifested as either non-cycling or cycling persisters. [NWM2] Mechanistically, transcriptomics identified that the combination of ziftomenib and irinotecan resulted in depression of polycomb targets that more strongly targeted cycling persister cells.
Conclusion:
Our work highlights that menin may be required for tumor cells to form a persister cell state, which creates a vulnerability that can be targeted by menin inhibition. Future work focusing on understanding how ziftomenib influences epigenetic plasticity during chemotherapy persistence and investigating the translational impact of menin inhibition will inform translational opportunities.
Citation Format:
Abhishek Wahi, Emily A. Cmarik, Jennifer E. Sturgis, Nathaniel W. Mabe. Targeting Neuroblastoma Persister Cells with Menin Inhibition Combined with Chemotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Bridging Discovery and Clinical Impact in Pediatric Cancer; 2026 Sep 22-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_1):Abstract nr B022.