Prevention of neuroblastoma with histone deacetylase inhibitors

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DESCRIPTION (provided by applicant): Cancer is the second commonest cause of childhood death. Neuroblastoma is the most common solid tumor in early childhood. Neuroblastoma due to MYCN oncogene amplification accounts for about one third of the disease and represents a more aggressive subtype with a worse clinical outcome. There is a pressing need for better understanding of neuroblastoma initiation, for more effective agents with a lower side-effect profile, and more ideally for effective chemo-prevention. Histone deacetylase (HDAC) over-expression induces histone hypo-acetylation and transcriptional repression, and is involved in both initiation and progression of some haematological malignancies and solid tumors. HDAC inhibitors (HDACIs) are highly effective against a wide variety of cancer types in some heavily pre-treated and multiply relapsed patients with a surprisingly low side-effect profile in clinical trials. We have recently found that MYCN induces HDAC2 over-expression in neuroblastoma cells, that HDAC2 over-expression in neuroblast cells precedes malignant transformation in MYCN transgenic mice, and that MYCN-modulated transcriptional repression is reversed by HDACIs. Our results suggest that MYCN-induced HDAC2 over-expression may be responsible for MYCN-induced transcriptional repression and may play an important role in MYCN induced tumorigenesis. In this application we seek to determine whether and how HDAC2 over-expression induces neuroblastoma, and whether early intervention with HDACIs prevents neuroblastoma initiation. Aims: To identify the role of HDAC2 over-expression in MYCN-induced tumorigenesis and whether early intervention with HDACIs prevents neuroblastoma initiation. Research design and methods: (i) Does MYCN down-regulate target gene expression through up-regulating HDAC2? (ii) Does HDAC2 over-expression correlate with MYCN-induced neuroblastoma initiation? (iii) Does HDAC2 over-expression correlate with MYCN-induced angiogeneis? (iv) Do HDACIs prevent neuroblastoma initiation in homozygous MYCN transgenic mice?