Targeting MYCN in Molecularly Defined Malignant Brain Tumors

Abstract

Misregulation of MYC genes, causing MYC overexpression or protein stabilization, is frequently found in malignant brain tumors highlighting their important roles as oncogenes. Brain tumors in children are the most lethal of all pediatric malignancies and the most common malignant primary adult brain tumor, glioblastoma, is still practically incurable. MYCN is one of three MYC family members and is crucial for normal brain development. It is associated with poor prognosis in many malignant pediatric brain tumor types and is focally amplified in specific adult brain tumors. Targeting MYCN has proved to be challenging due to its undruggable nature as a transcription factor and for its importance in regulating developmental programs also in healthy cells. In this review, we will discuss efforts made to circumvent the difficulty of targeting MYCN specifically by using direct or indirect measures to treat MYCN-driven brain tumors. We will further consider the mechanism of action of these measures and suggest which molecularly defined brain tumor patients that might benefit from MYCN-directed precision therapies.

Clinically aggressive pediatric spinal ependymoma with novel MYC amplification demonstrates molecular and histopathologic similarity to newly described MYCN-amplified spinal ependymomas

“…Deregulation of MYC has been shown to stimulate and maintain tumorigenesis in ex vivo models [ 28 , 48 ]. MYC alterations are recurrently described amongst many different types of neoplasms, including pediatric brain tumors [ 6 , 25 ], with amplification being most frequently reported [ 25 , 28 ]. Glial and non-glial brain tumors harboring MYC amplification demonstrated a significantly worse prognosis [ 8 , 22 , 27 , 30 , 37 , 42 , 54 ].…”

Identification of Let-7 miRNA Activity as a Prognostic Biomarker of SHH Medulloblastoma

“…MYCN-amplified SHH-MB is generally resistant to SMO inhibitors, a targeted therapy for SHH-MB [ 18 , 19 , 79 ]. It has been suggested that DFMO would have a greater effect on MYCN-amplified tumors [ 80 ].…”

“…The overall survival rates of the four MB subgroups were not significantly different ( Supplementary Figure S10 ), and SHH-MB was the most heterogeneous subgroup among the four MB subgroups [ 12 ]. SMO inhibition is a targeted therapy for SHH-MB, but SHH-MB patients with high MYCN expression were resistant to SMO inhibitors in general [ 18 , 19 , 79 ]. Furthermore, p53 mutations are associated with MYCN amplification and are implicated in conferring resistance to both radiation therapy and SMO inhibitors in SHH-MB [ 22 , 23 , 24 , 25 ].…”

MYCN in Neuroblastoma: “Old Wine into New Wineskins”

“…It has been shown, in multiple reports, that MYCN overexpression is directly associated with poor prognosis of neuroblastoma and it is thought that there is a strong correlation between gene overexpression and the evolutionary course of tumors [ 8 ]. On the other hand, MYCN has received less attention with respect to pediatric brain tumors, while recent reports have highlighted its role in the disease [ 9 , 10 , 11 ]. Apart from its role in neuroblastoma, MYCN has been studied in some extent for other pediatric brain neoplasms such as medulloblastoma [ 12 , 13 ], astrocytoma [ 14 ], glioblastoma [ 15 , 16 ], and others.…”

“…The MYCN oncogene is one of the most important genetic biomarkers for the diagnosis, prognosis and treatment of neuroblastoma. MYCN overexpression is associated with poor prognosis and rapid tumor growth [ 9 , 17 , 18 ]. However, it does not function as a unique f actor rather it is reported to participate in a network of other factors, procuring neuroblastoma’s pathology.…”