# Masters of Gene Expression: Transcription Factors in Pediatric Cancers

## TL;DR

Transcription factors play a key role in pediatric cancers and targeting them could lead to better, less toxic treatments for children.

## Contribution

This review highlights the role of transcription factors in pediatric cancers and emphasizes new therapeutic strategies targeting them.

## Key findings

- Transcription factors are frequently disrupted in pediatric cancers despite low mutation rates.
- Dysregulation of transcription factors disrupts gene expression and promotes tumor growth.
- New therapies like PROTACs and molecular glue degraders offer promising treatment options.

## Abstract

Transcription factors (TFs) are proteins that directly regulate gene expression and are crucial for cell development and differentiation. When TFs become abnormally active, they can drive uncontrolled cancer growth and survival. Frequent disruption of TFs is a striking feature of pediatric cancers, despite their low overall mutation burden. These altered TFs interfere with normal lineage programs and “hijack” developmental signaling pathways, creating self-sustaining loops that promote tumor growth. Studying TFs is therefore essential. It helps identify biomarkers for diagnosis, predict treatment responses, and develop therapies that directly target TFs or their regulatory networks. These insights offer new opportunities to design more effective and less toxic treatments for pediatric patients.

Childhood cancer is rare, with about 1 in 260 children developing cancer before age 20. However, it remains a leading cause of death for children and adolescents worldwide. The 5-year survival rate for childhood cancer in high-income countries exceeds 80%, but globally, the average survival rate is around 37%, highlighting significant disparities across the globe. Despite the life-saving impact of current treatment regimens, long-term side effects and risks are always concerns. Therefore, there is a continuing urgent need for novel therapies to overcome the limitations of existing approaches and improve patient outcomes. Targeted drug therapies that interfere with cancer-causing genes play a vital role in cancer treatment by specifically targeting cancer cells. TFs are primary drivers of gene expression that are critical in various pediatric cancers. Chromosomal rearrangements, involving changes in chromosome structure such as deletions, duplications, inversions, and translocations, can significantly alter TF activity and downstream gene expression. Dysregulation of TFs disrupts gene expression networks and has been strongly linked to the development and progression of many pediatric cancers, making them promising therapeutic targets. Several approaches targeting TFs, including small-molecule inhibitors designed to block TF-DNA binding, TF-cofactor interactions, or their epigenetic regulation, as well as RNA interference, have been developed. More recently, approaches like PROTACs (Proteolysis-Targeting Chimeras) and molecular glue degraders offer new therapeutic possibilities in pediatric cancers. These innovations represent a paradigm shift in pediatric oncology, offering hope for more targeted, less toxic treatment options. This review discusses the critical role of TFs in childhood cancers and emphasizes the need for evolving therapeutic strategies aimed at targeting these key regulators to improve outcomes for young patients.