Targeting specific protein regions offers a new treatment approach in medulloblastoma

Medulloblastoma (the most common malignant childhood brain tumor) is separated into four molecular groups, with Group 3 bearing the worst prognosis. By studying EP300 and CBP, critical proteins in Group 3 medulloblastoma cells, scientists at St. Jude Children’s Research Hospital designed a way to enhance anti-tumor activity by targeting a specific part of these proteins. This targeted approach significantly reduced cancer cell growth. The findings were reported today in Nature Communications.

Previous research by St. Jude scientists and others has classified medulloblastoma into four distinct molecular groups: WNT and SHH — driven by their namesake genetic mutations — Group 3 and Group 4. The prognosis for medulloblastoma is different for each molecular group. Retrospective analyses have shown that WNT tumors have 95% five-year survival. SHH and Group 4 tumors have approximately 75% five-year survival, and the survival rate for Group 3 is only 60%. Approximately one-third of all patients with medulloblastoma relapse, but the rate of relapse varies based on factors such as the patient’s age and what type of therapy they receive.

Scientists often pharmaceutically target specific domains, or regions, of tumor proteins to inhibit cancer cell growth. EP300 and CBP are highly similar proteins that drive cancer cell growth and, therefore, tumor progression, making them attractive targets for therapy.

“EP300/CBP have different domains that have small molecules that bind to them and can disrupt their function,” said Adam Durbin, MD, PhD, Department of Oncology. “We wanted to understand if targeting these proteins in specific ways would be more effective. We saw that disrupting individual domains was not equal in how it affects cancer cells.”

Targeting two different parts of the same proteins

The researchers identified inhibitors that can interact with either of two specific regions of EP300/CBP: the histone acetyltransferase (HAT) domain and the bromodomain. Using high-throughput cell line–based screening, the team tested these region-specific inhibitors across over 400 different cancer cell lines. They found that bromodomain inhibition with a compound called inobrodib was more effective at killing Group 3 medulloblastoma cells than targeting the HAT domain.

“The effects of bromodomain targeting of EP300/CBP are profound, causing the inactivation of a network of genes that Group 3 medulloblastoma cells critically require to survive,” said first author Noha Shendy, PhD, St. Jude Department of Oncology.

Think of the HAT and the bromodomain regions of EP300/CBP as two light switches in a room, controlling different lights — one for overhead and one for a lamp. Now, consider drugs as being able to toggle these switches on and off. Turning off the overhead light is different than turning off the lamp, but each causes the room to be dimmer. Similarly, when drugs bind to the two regions of EP300/CBP, they modify the activity of these regions, influencing the “brightness” of different cellular processes regulated by these proteins.

The researchers found that using inobrodib to disrupt the activity of the bromodomain region in Group 3 medulloblastoma cells was especially effective at slowing tumor cell growth. Bromodomain inhibition decreased the “brightness,” thereby inactivating Group 3 medulloblastoma tumor-promoting genes and offering a potential therapeutic benefit.

“We found a new target that is druggable in this aggressive pediatric brain tumor that we’re continuing to study to try to help patients,” noted Durbin.