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Cancer Res ; 81(7): 1627-1632, 2021 04 01.
Article in English | MEDLINE | ID: mdl-33509943

ABSTRACT

Effective treatment of pediatric solid tumors has been hampered by the predominance of currently "undruggable" driver transcription factors. Improving outcomes while decreasing the toxicity of treatment necessitates the development of novel agents that can directly inhibit or degrade these elusive targets. MYCN in pediatric neural-derived tumors, including neuroblastoma and medulloblastoma, is a paradigmatic example of this problem. Attempts to directly and specifically target MYCN have failed due to its similarity to MYC, the unstructured nature of MYC family proteins in their monomeric form, the lack of an understanding of MYCN-interacting proteins and ability to test their relevance in vivo, the inability to obtain structural information on MYCN protein complexes, and the challenges of using traditional small molecules to inhibit protein-protein or protein-DNA interactions. However, there is now promise for directly targeting MYCN based on scientific and technological advances on all of these fronts. Here, we discuss prior challenges and the reasons for renewed optimism in directly targeting this "undruggable" transcription factor, which we hope will lead to improved outcomes for patients with pediatric cancer and create a framework for targeting driver oncoproteins regulating gene transcription.


Subject(s)
Antineoplastic Agents/isolation & purification , Drug Resistance, Neoplasm , N-Myc Proto-Oncogene Protein/physiology , Neoplasms/drug therapy , Therapies, Investigational , Age of Onset , Antineoplastic Agents/history , Antineoplastic Agents/therapeutic use , Child , Drug Discovery/history , Drug Discovery/methods , Drug Discovery/trends , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , Drug Screening Assays, Antitumor/history , Drug Screening Assays, Antitumor/methods , Drug Screening Assays, Antitumor/trends , Gene Expression Regulation, Neoplastic/drug effects , History, 20th Century , History, 21st Century , Humans , N-Myc Proto-Oncogene Protein/antagonists & inhibitors , N-Myc Proto-Oncogene Protein/genetics , Neoplasms/epidemiology , Neoplasms/genetics , Therapies, Investigational/history , Therapies, Investigational/methods , Therapies, Investigational/trends
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