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*For medical professionals only
Treatment strategies for BRD8 can be used to treat most patients with
glioblastoma.
Executive Summary
On December 21, 2022, a new study published in the journal Nature revealed that BRD8 protein overactivity is an important cause of glioblastoma's pathogenesis, which provides new strategies
for controlling, treating and even curing glioblastoma.
Study screenshots
status quo
.
According to statistics, the incidence of glioblastoma worldwide is about 3.
2 per 100,000 people, and the number of
new patients reaches 256,000 every year.
The clinical symptoms of glioblastoma are mainly headache, vomiting, vision loss and incontinence, which seriously affect the quality of life
of patients and families.
With a median survival of only 12-14 months and a 5-year survival rate of less than 5%, glioblastoma patients remain one of
the most difficult cancers to treat at the global level.
This statistic has not improved
for decades due to the lack of effective clinical treatment.
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 exhibit mutations and failures
of P53.
But curiously, while P53 is normally expressed in most GBM cases, GBM exhibits a tumor phenotype
in which P53 is disrupted.
conclusion
Alea Mills, the first author of the study and professor at the Cancer Center of the Cold Spring Harbor Laboratory (CSHL) in the United States, found that the tumor transcriptomics data of 452 GBM patients found an important protein that regulates P53: bromodomain-containing protein 8 (BRD8).
The molecular mechanism
of BRD8 regulation of P53 was further analyzed by RNAseq and animal-level studies.
The results of the study showed:
- Among the 452 GBM patients who underwent transcriptomic analysis, 71% of patients had no mutation in P53 (P53WT), and compared with the mutant GBM patients, the target gene CDKN1A of P53 had loss of function, suggesting that regardless of whether P53 was mutated, the function of P53 protein in GBM patients was inhibited, and BRD8, the protein BRD8, which was most relevant to regulating P53 epigenetics, was mined through further database comparison.
- BRD8 protein is abnormally active in glioblastoma, and inhibits P53 gene activity and weakens P53 protein function through the "lock and key mechanism" combined with unacetylated H2AZ, in other words, the presence of BRD8 protein will induce GBM;
- When BRD8 is inactivated by genome editing, the unmutated P53 gene in GBM is reactivated and begins to stop tumor growth;
- In animal tests, the P53 gene of GBM implanted in the brains of mice was "unlocked" when the BRD8 protein was inactivated, the tumors stopped growing, and the life span of mice was extended
.
prospect
This study identified the mechanism by which BRD8 protein regulates P53 gene activity in GBM, which may provide an effective strategy
for the treatment of P53WT GBM.
Alea Mills noted:
- With these findings, we can then design small molecules to disrupt this interaction, which may be used as a new therapeutic strategy for glioblastoma;
- This treatment that targets the BRD8 gene is highly effective as long as the P53 gene in the patient's body is still functioning, and as far as we know, this is the case in about 71% of GBM patients
.
That is, treatment strategies targeting BRD8 can be used to treat most patients with
glioblastoma.
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