Atypical teratoid/rhabdoid tumor (ATRT) is a rare and highly aggressive pediatric brain tumor. It typically affects kids 3 years and younger. The 5-year overall survival rate for kids with ATRT is about 30%. The standard treatment for ATRT is chemotherapy and radiation, which can improve outcomes, but leaves kids with significant long-term side effects.

The poor outcome for kids with ATRT has not changed in recent years, so doctors and researchers are continually searching for a treatment that will give them a better chance at survival.

ATRT tumors are primarily characterized by a genetic mutation where the SMARCB1 gene is not present. The SMARCB1 gene is part of a chromatin remodeling complex that regulates gene expression. The loss of SMARCB1 results in epigenetic dysregulation of the patient’s genome.

Dr. Rajeev Vibhakar and senior researcher Irina Alimova have been investigating the ways ATRTs form and grow in the brain, so that a weakness can be identified and exploited.

Last year, they identified a protein called BMI1 as a key regulator of ATRT, which had not previously been evaluated in ATRT. They proved that inhibiting BMI1 is a possible avenue for treating kids with ATRT and then they began working to understand how BMI1 cooperates with the missing SMARB1 gene.

The research team confirmed that the expression of BMI1 is elevated in patients with all three subgroups of ATRT. BMI1 has an effect on stem cell behavior in both normal and malignant cells, which is important because stem cells have the ability to self-renewal and differentiate into specialized adult cells.

Researchers then tested and showed that when BMI1 is depleted through genetic knockdown, ATRT cell growth and proliferation are highly suppressed in both in vitro and in vivo experiments.

From there, the team has been testing a new drug called PTC596 that chemically inhibits BMI1. They started with an in vitro model using ATRT cell lines and found that PTC596 decreased tumor cell proliferation and colony formation.

The team then moved to an in vivo animal model and have seen encouraging results. Treatment with the PTC596 drug inhibited  ATRT tumor growth, leading to reduced tumor volume and increased survival. Median survival in the control group was 21 days compared to 48 days for the group treated with PTC596, representing a 128% increase in survival.

Researchers are currently investigating the ways in which genetic BMI1 inhibition is different from chemical BMI inhibition.

They have shown that genetic inhibition of BMI1 affects the cell cycle, specifically the stage where the cell is preparing to divide and replicate. With chemical inhibition of BMI1, the team has proven that the drug PTC596 activates apoptosis, which is the body’s normal and controlled process of cell death.

This approach of treating ATRT by inhibiting BMI1 with the drug PTC596 may hold the key for kids diagnosed with this deadly tumor.