Prevention of neuroblastoma with histone deacetylase inhibitors

描述（由申请人提供）： 癌症是儿童死亡的第二大常见原因。神经母细胞瘤是儿童早期最常见的实体瘤。由于MYCN癌基因扩增引起的神经母细胞瘤约占疾病的三分之一，并且代表具有更差临床结果的更具侵袭性的亚型。迫切需要更好地了解神经母细胞瘤的发生，更有效的药物，更低的副作用，更理想的是有效的化学预防。组蛋白去乙酰化酶（HDAC）的过表达可诱导组蛋白低乙酰化和转录抑制，并参与某些血液系统恶性肿瘤和实体瘤的发生和发展。HDAC抑制剂（HDACIs）在一些重度预治疗和多次复发的患者中对多种癌症类型非常有效，在临床试验中副作用非常低。我们最近发现，MYCN诱导HDAC2在神经母细胞瘤细胞中的过度表达，在MYCN转基因小鼠中，神经母细胞中HDAC2的过度表达先于恶性转化，并且MYCN调节的转录抑制被HDACIs逆转。我们的研究结果表明，MYCN诱导的HDAC2过表达可能是MYCN诱导的转录抑制，并可能在MYCN诱导的肿瘤发生中发挥重要作用。在本申请中，我们试图确定HDAC2过表达是否以及如何诱导神经母细胞瘤，以及HDACIs的早期干预是否阻止神经母细胞瘤的发生。目的：确定HDAC2过表达在MYCN诱导的肿瘤发生中的作用，以及HDACIs的早期干预是否可以预防神经母细胞瘤的发生。研究设计和方法：（i）MYCN是否通过上调HDAC 2下调靶基因表达？(ii)HDAC2过表达与MYCN诱导的神经母细胞瘤发生相关吗？(iii)HDAC2过度表达与MYCN诱导的血管生成相关吗？(iv)HDACIs能预防纯合子MYCN转基因小鼠中神经母细胞瘤的发生吗？

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?