Biological Role of MYCN in Medulloblastoma: Novel Therapeutic Opportunities and Challenges Ahead

Abstract

The constitutive and dysregulated expression of the transcription factor MYCN has a central role in the pathogenesis of the paediatric brain tumour medulloblastoma, with an increased expression of this oncogene correlating with a worse prognosis. Consequently, the genomic and functional alterations of MYCN represent a major therapeutic target to attenuate tumour growth in medulloblastoma. This review will provide a comprehensive synopsis of the biological role of MYCN and its family components, their interaction with distinct signalling pathways, and the implications of this network in medulloblastoma development. We will then summarise the current toolbox for targeting MYCN and highlight novel therapeutic avenues that have the potential to results in better-tailored clinical treatments.

Phosphorylation of MYCN and MAX by PAK family kinases is a novel tumor-suppressor mechanism in neuroblastoma with potential therapeutic implications

“…1B). Because of its oncogenic potential, the Myc gene is tightly regulated at transcriptional (5-7), posttranscriptional (8,9), and posttranslational (10) levels.…”

“…N-myc-amplified neuroblastomas follow a very aggressive course (6). Overexpression of transfected N-myc genes in neuroblastoma cell lines strongly increased proliferation rates (7,8). Recent mRNA expression profiling experiments, serial analysis of gene expression (SAGE) and microarray analysis, identified many myc-regulated genes (9)(10)(11)(12)(13).…”

“…Four genes mapping to chromosome lp36 have been proposed as candidate neuroblastoma suppressor genes: ID3 (heir-i), a neuroectodermally expressed member of the Id family of developmental negative regulatory genes (5); TNFR2, one of two tumor necrosis factor receptor genes (6); CDC2L1 homology to human CDC2 (7); and DAN, a transcription factor gene homologous to a mouse tumor suppressor gene (8). Two additional genes, the transcriptional regulator E2F2 and the paired-box-containing gene PAX7, have recently been mapped to lp36 (9, 10) and are thus potential candidate suppressor genes.…”

“…MYCN belongs to the MYC family of oncogenes, which includes three closely related genes, c-MYC, MYCN and MYCL 6,7 . Amplification of the MYCN gene is predominantly found in neuroendocrine tumors, including neuroblastoma, medulloblastoma, retinoblastoma and neuroendocrine prostate cancer 8–10 . MYCN amplification is an initiating event, driving the development of high-risk neuroblastoma.…”

Medulloblastoma oncogene aberrations are not involved in tumor initiation, but essential for disease progression and therapy resistance

“…4f ). Upon malignant transformation of the tumor’s MRCA, we assume exponential growth until a tumor size of 10 9 cells (corresponding to a few cubic centimeters) is reached at the age of diagnosis (see Methods for details 22 ). By fitting this model to the clonal SNV densities measured in Group 3/4 medulloblastomas, we inferred that the first oncogenic event ( i.e ., the ECA) occurs within the first gestational trimester in 24% of the cases, during late gestation in around 35% of cases and within the first year of life in 20% of cases ( Extended Data Fig.…”