Abstract
Lysine-Specific Demethylase 1 (LSD1) over-expression correlates with poorly differentiated neuroblastoma and predicts poor outcome despite multimodal therapy. We have studied the efficacy of reversible and specific LSD1 inhibition with HCI-2509 in neuroblastoma cell lines and particularly the effect of HCI-2509 on the transcriptomic profile in MYCN amplified NGP cells. Cell survival assays show that HCI-2509 is cytotoxic to poorly differentiated neuroblastoma cell lines in low micromole or lower doses. Transcriptional profiling of NGP cells treated with HCI-2509 shows a significant effect on p53, cell cycle, MYCN and hypoxia pathway gene sets. HCI-2509 results in increased histone methyl marks and p53 levels along with cell cycle arrest in the G2/M phase and inhibition of colony formation of NGP cells. Our findings indicate that LSD1 inhibition with HCI-2509 has a multi-target effect in neuroblastoma cell lines, mediated in part via p53. MYCN-amplified neuroblastoma cells have a targeted benefit as HCI-2509 downregulates the MYCN upregulated gene set.
Highlights
Neuroblastoma is the most common extracranial solid tumor in childhood
These results suggest that Lysine-Specific Demethylase 1 (LSD1) inhibition is likely to be an effective therapeutic strategy in poorly differentiated neuroblastoma regardless of MYCN amplification status
Because MYCN overexpression has been identified as a strong predictor of poor outcomes in neuroblastoma we investigated the effects of HCI-2509 on NGP cells- a MYCN amplified neuroblastoma cell line
Summary
Neuroblastoma is the most common extracranial solid tumor in childhood. More than 650 cases of neuroblastoma are diagnosed each year in North America [1]. The clinical course of neuroblastoma ranges from low-grade disease with spontaneous remission to high-grade disease with poor outcome. Chemotherapy, radiation, myeloablative therapy followed by autologous hematopoietic stem cell transplant, antiGD2 antibody, Interleukin-2, GM-CSF and retinoic acid [2]. The 5-year survival rate for children diagnosed with neuroblastoma from 2006-2012 was estimated to be close to 77 percent [3]. The 5-year survival rate for children with neuroblastoma in the high-risk group (risk category per the Children’s Oncology Group criteria) is only 40% to 50% [4]
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