The MYCN Oncogene as a Specific and Selective Drug Target for Peripheral and Central Nervous System Tumors
MYCN belongs to the MYC family of proto-oncogenes, which encode for transcription factors of the basic-helix-loop-helix-zipper (bHLHZ) class and is fundamental in the development of the peripheral and central nervous systems (PNS and CNS). While Myc is ubiquitous, MYCN has a very restricted expression pattern: it is mainly expressed during embryonic development, but then becomes downregulated, while in adults it is usually detected in B-cell development. Identification of selective inhibitors of MYCN and its mRNA and protein could be important for the development of more specific, effective and less toxic therapeutic agents for tumors of the PNS and CNS. In children, the most common tumors of the PNS and CNS are neuroblastomas and medulloblastomas, respectively. About 30% of neuroblastoma (NB) tumors present MYCN amplification/over-expression, which is associated with rapid progression and poor prognosis. N-Myc is essential during neurogenesis for the rapid expansion of progenitor cells in the brain. MYCN amplification and over-expression has been reported in medulloblastoma, and especially in the desmoplastic type. Other tumors associated with MYCN overexpression include retinoblastoma, small cell lung carcinoma, glioblastoma and certain embryonal tumors. A cell-based, N-Myc-dependent luciferase reporter gene assay to identify specific N-Myc small-molecule inhibitors has allowed identification of five compounds showing significant activity. Antisense oligodeoxynucleotides have been shown to inhibit N-Myc production and anti-tumoral activity in vitro and in vivo for NB. Peptide nucleic acids (PNA), which belong to the most recent (third) generation of nucleic acid therapeutics, form highly stable duplexes with DNA and RNA, and are resistant to degradation by nucleases and proteases. Encouraging results have been reported utilizing a PNA-based antisense strategy for inhibition of N-Myc expression in neuroblastoma.
Keywords: mycn, gene amplification, neuronal tumors, small molecules, antisense oligonucleotides, triplex forming oligonucleotides, peptide nucleic acids, immunotherapy
Rights & PermissionsPrintExport