MYCN Impact on High-Risk Neuroblastoma: From Diagnosis and Prognosis to Targeted Treatment

Abstract

Among childhood cancers, neuroblastoma is the most diffuse solid tumor and the deadliest in children. While to date, the pathology has become progressively manageable with a significant increase in 5-year survival for its less aggressive form, high-risk neuroblastoma (HR-NB) remains a major issue with poor outcome and little survivability of patients. The staging system has also been improved to better fit patient needs and to administer therapies in a more focused manner in consideration of pathology features. New and improved therapies have been developed; nevertheless, low efficacy and high toxicity remain a staple feature of current high-risk neuroblastoma treatment. For this reason, more specific procedures are required, and new therapeutic targets are also needed for a precise medicine approach. In this scenario, MYCN is certainly one of the most interesting targets. Indeed, MYCN is one of the most relevant hallmarks of HR-NB, and many studies has been carried out in recent years to discover potent and specific inhibitors to block its activities and any related oncogenic function. N-Myc protein has been considered an undruggable target for a long time. Thus, many new indirect and direct approaches have been discovered and preclinically evaluated for the interaction with MYCN and its pathways; a few of the most promising approaches are nearing clinical application for the investigation in HR-NB.

Comparing Tribbles Homolog 3 (TRIB3) Protein Expression Levels with Clinicopathological Characteristics and Survival Among Neuroblastoma Patients

“…MYCN amplification is a well-established prognostic marker for NB related to advanced disease phenotype. 26 However, no significant correlation between TRIB3 expression and MYCN amplification was detected in our patient cohort. Instead, a significant correlation between TRIB3 and 1p36 LOH was identified among patients.…”

Kinases Controlling Stability of the Oncogenic MYCN Protein

“…We sought to investigate the potential of PI3K and CK2 as key kinases that control MYCN stability and by which pomiferin and isopomiferin may exert their MYCN-ablating activity, making them potential targets for intervention. 3 Pomiferin is a natural product found in the Osage orange. Pomiferin and its analogue isopomiferin are not readily available commercially and must be purified from the fruit, which is a tedious process with low yield.…”

“…2 MYCN is amplified in about 25% of NBL cases, generally those that are aggressive and high-risk with poor outcomes. 3 MYCN is localized to the tissue of the brain and kidney and present solely during developmental stages. 2 The correlation between MYCN expression and NBL prognosis makes it a promising target for therapy.…”

“…One method of overcoming this drawback is to intervene in the pathways regulating such oncoproteins. We sought to investigate the potential of PI3K and CK2 as key kinases that control MYCN stability and by which pomiferin and isopomiferin may exert their MYCN-ablating activity, making them potential targets for intervention …”

MYCN mRNA degradation and cancer suppression by a selective small-molecule inhibitor in MYCN-amplified neuroblastoma

“…In addition, the structure of MYCN is composed almost entirely of α helices with no surface for ligand binding and molecular targeting. Due to the complex functions of MYCN protein and the difficulty for targeting, attempts to selectively inhibit MYCN protein for therapy of MYCN -amplified NB tumors have met with little success ( 6 ).…”