It Turns out that p53 is Destroyed in a Whole New Way

Glioblastoma is a deadly brain cancer with a dire prognosis. Unlike most cancers, it still grows in the presence of the p53 protein. Scientists have been unable to solve the case for decades...until now. CSHL scientists have discovered that a protein called BRD8 goes out of control in glioblastoma, paralyzing P53. The discovery could help turn this deadly cancer into a treatable disease.

Brain cancer, glioblastoma, is a fierce and formidable adversary. Among the millions of victims, including Senator John McCain, President Biden's son and famous film critic Gene Siskel, most patients died within two years, and few survived five years due to lack of effective treatment options, a statistic that has not improved in decades.

"Glioblastomas are notoriously aggressive," said Professor Alea Mills of Cold Spring Harbor Laboratory (CSHL). "The norm is to do surgery, treat with strong drugs, and hope for the best." But now, Mills and her colleagues have identified a vulnerability in this deadly cancer known as BRD8, which may ultimately lead to new treatment options and better patient outcomes.

The CSHL team recently solved a decades-old mystery surrounding the aggressiveness of glioblastoma by linking the BRD8 protein to another protein called p53. P53 is a major component of the body's natural cancer defense system, which prevents cells from overgrowing and turning into tumors. Almost all cancers depend on mutations and failures of p53. But strangely, in most glioblastoma cases, p53 remained unharmed. So, why does this cancer behave as if p53 is disrupted? This key question led Mills' team to discover that BRD8 goes out of control in glioblastoma, disrupting p53 in a completely new way.

BRD8 shuts off access to genes in chromosomes. If a gene is tightly coiled, it cannot be used—it is as if it is "asleep". The team found that BRD8 is extraordinarily active in glioblastoma, putting many of p53's key anticancer defenses in quiescence. When the researchers inactivated BRD8 through genome editing, the p53 arsenal suddenly came to life and began to stop tumor growth.

"It's like BRD8 saying 'NO ENTRY' to the tumor-preventive power of p53, but when we attack BRD8 in the right way— almost like a scalpel in there, but molecularly—the tumor is wiped out," Mills explained up. She and her team implanted tumor cells from glioblastoma patients into mice and watched the tumors grow in the brain. When BRD8 was inactivated, p53 was unlocked—the tumors stopped growing and the mice lived longer.

This finding suggests that drugs targeting the heart of BRD8 may be effective against glioblastoma. Mills hopes her team's discovery will help turn this deadly brain cancer into a treatable disease and, for the first time in a generation, increase the life expectancy of patients diagnosed with the disease.