The MYCN Oncogene as a Specific and Selective Drug Target for Peripheral and Central Nervous System Tumors

Abstract

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.

Effect on Cell Cycle Progression by N-Myc Knockdown in SK-N-BE(2) Neuroblastoma Cell Line and Cytotoxicity with STI-571 Compound

“…MYCN amplification occurs in approximately 25% of neuroblastoma cases (7), and is associated with cancer progression and treatment failure (8). Although the linkage between the mechanism of N-Myc overexpression and more aggressive neuroblastoma phenotypes remains to be elucidated, MYCN clearly induces cell growth via transcriptional activation of the target genes ODC, MCM7, MDM2, MDR1, or PAX3, and is involved in the progression of the G1-S phase, bypassing the G1 checkpoint (9). As MYCN-expressing cancer cells often evidence defects in the apoptotic pathway, the inhibition of MYCN expression may prove to be a useful target for neuroblastoma treatment.…”

Overview and recent advances in the treatment of neuroblastoma

“…Because of the association of MYCN amplification with high-risk cases of neuroblastoma, it represents an attractive potential therapeutic target [152], and numerous efforts to develop MYCN inhibitors have been made in the past. However, as a nuclear transcription factor, MYCN is difficult to target therapeutically.…”

Antitumor Activity of Sustained N-Myc Reduction in Rhabdomyosarcomas and Transcriptional Block by Antigene Therapy

“…However, therapeutic targeting of nuclear transcription factors such as those of the Myc-family is considered challenging. Oligonucleotides in clinical trials are based on antisense approaches which target mRNA and inhibit translation, whereas less well-known antigene strategies target the chromosomal DNA and inhibit transcription (13,(17)(18)(19)(20)(21)(22). Antigene approaches offer conceptual advantages over antisense: usually two gene copies per cell to target rather than multiple copies of mRNA that are continually being transcribed; a persistence block of the transcriptional process; and simultaneous inhibition of all splice variants and their simple and nonrestrictive design (13,(17)(18)(19)(20)(21)(22).…”

“…Oligonucleotides in clinical trials are based on antisense approaches which target mRNA and inhibit translation, whereas less well-known antigene strategies target the chromosomal DNA and inhibit transcription (13,(17)(18)(19)(20)(21)(22). Antigene approaches offer conceptual advantages over antisense: usually two gene copies per cell to target rather than multiple copies of mRNA that are continually being transcribed; a persistence block of the transcriptional process; and simultaneous inhibition of all splice variants and their simple and nonrestrictive design (13,(17)(18)(19)(20)(21)(22). In keeping with requirements for clinical application, peptide nucleic acid (PNA) oligonucleotides (23) show potent antigene activity (13,17,18,21) and are resistant to nucleases and proteases although their in vivo potential has not been shown.…”