SIRT2 Inhibition Shows Promise Against Atypical Teratoid Rhabdoid Tumors (ATRT)

Research study background

Neuro-oncology researchers from the Morgan Adams Foundation Pediatric Brain Tumor Research Program at Children’s Hospital Colorado recently published preclinical findings highlighting a promising new therapeutic strategy for atypical teratoid rhabdoid tumors (ATRT). With a survival rate of approximately 35%, these aggressive and highly malignant central nervous system tumors that predominantly affect young children urgently need more effective, druggable targets. 

ATRT is driven by the loss of the SMARCB1 gene, which regulates gene expression (also called epigenetic regulation). Its absence disrupts normal cell development and promotes tumor growth. In this study, investigators hypothesized that other epigenetic factors might also be involved in ATRT survival and growth when SMARCB1 is missing. A broad screening to identify related genes that may work with SMARCB1 pinpointed the protein SIRT2 as a key regulator.

The team conducted various experiments, including in vitro assays that tested the effects of SIRT2 inhibition on ATRT cell self-renewal and differentiation. They found that ATRT cells depend on SIRT2 for their growth and survival. When SIRT2 levels were inhibited or reduced in laboratory settings, the ATRT cells exhibited less growth and potential for differentiation, suggesting that SIRT2 helps maintain these cancer cells in an undifferentiated state. Researchers also evaluated novel SIRT2 inhibitors including thiomyristoyl (TM), which was found to be very potent and effective. TM treatment not only decreased ATRT cell survival but also encouraged differentiation into more specialized cell types.

To explore if SIRT2 inhibition could be used for therapeutic effect in vivo, researchers administered TM or a vehicle control to randomized orthotopic murine models. The results were compelling — compared to vehicle controls, TM-treated mice demonstrated significant reductions in tumor growth, improved differentiation of cancer cells and notably, a significant improvement in overall survival.

Clinical implications

This study deepens the understanding of how SIRT2 functions within ATRT cells and highlights the importance of SIRT2 for the survival of ATRT cells missing SMARCB1. These findings suggest the potential of SIRT2 inhibition as an effective treatment approach for these challenging pediatric brain tumors. Study authors plan to conduct follow-up studies to validate these findings. Through additional investigations and clinical trials of SIRT2 inhibitors, researchers hope to develop innovative therapies that improve outcomes for children with atypical teratoid rhabdoid tumors.