Glioblastoma is an aggressive type of brain cancer. It has claimed the lives of millions of people, including Senator John McCain, President Joe Biden’s son Beau, and legendary film critic Gene Siskel. Most patients die within two years, and few make it to five years. This number hasn’t changed in decades because there aren’t any good treatments.

“The aggressiveness of glioblastoma is notorious,” remarks Professor Alea Mills from Cold Spring Harbor Laboratory (CSHL). “The norm is to do surgery, treat with harsh drugs, and just hope for the best.” 

But now, Mills and her colleagues have found a weakness in this deadly cancer called BRD8 that could lead to new ways to treat it and better outcomes for patients.

Scientists at CSHL have recently linked the BRD8 protein to another protein called P53, so shedding light on a decades-old riddle regarding the aggressiveness of glioblastoma. P53 is a key part of the body’s natural defenses against cancer. It stops cells from growing too much and turning into tumors. For cancer to develop, P53 must undergo mutation and become inactive. However, P53 remains remarkably unharmed in the vast majority of glioblastoma instances. 

Xueqin Sun, a postdoctoral associate at CSHL, wondered why “does this cancer act like P53 is broken?.”

This important question led Mills’ team to find out that BRD8 had gone rogue in glioblastoma, hurting P53 in a completely new way.

BRD8 blocks chromosome-based gene access. If a gene is tightly wrapped, it cannot be used; it is “asleep.” Mills and her colleagues discovered that BRD8 was overactive in glioblastoma, suppressing several of P53’s important anticancer defenses. When BRD8 was deactivated by genome editing, P53’s “arsenal” abruptly awoke and started inhibiting tumor development.

“It’s like BRD8 is saying ‘NO ENTRY’ to P53’s tumor-preventing power, but when we hit BRD8 in the right way—go in there almost like a scalpel, but molecularly—the tumor is annihilated,” explains Mills.  

She and her team put tumor cells from people with glioblastoma into mice and watched the brain tumors grow. When BRD8 was turned off, P53 was released. This stopped the growth of tumors and made the mice live longer.

This discovery raises the possibility that medications that target the core of BRD8 might be effective against glioblastoma.

Mills hopes that the discovery her team made will help turn this deadly brain cancer into a disease that can be treated and, for the first time in a generation, lengthen the lives of people who have it.

Source: 10.1038/s41586-022-05551-x

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