Shutting down a mysterious gene can help patients get rid of the deadliest brain cancer

The deadly brain cancer is no longer a mystery.
Rupendra Brahambhatt
Stock image of a man receiving radiotherapy for cancer treatment.
Stock image of a man receiving radiotherapy for cancer treatment.

Mark Kostich/iStock 

Glioblastoma is one of the most dangerous cancer types affecting the human brain and spinal cord. Over 240,000 people lose their lives because of nervous system cancer annually, and in most of these cases, the leading cause of death is glioblastoma. 

Its tumors spread fast and induce highly painful seizures and headaches. What’s worse is that there is no known 100 percent effective cure for this disease. US president Joe Biden’s eldest son Beau Biden and late American actor Robert Forster were also among the many victims of glioblastoma.

However, now a team of researchers at Cold Spring Harbor Laboratory (CSHL) in New York has figured out why glioblastoma is so aggressive in nature. They have also proposed a mechanism that could be employed to control and cure this deadly cancer in humans.

Solving the mystery behind glioblastoma

According to the researchers, by its occult nature, glioblastoma is deadly since it is not usually detected early. It tends to grow quickly and disrupt brain functions. When it all of a sudden appears, the normal treatment regimen is surgery, followed by chemo/radiation therapy. 

However, its many different cancer cells take on numerous forms. The various tumors in the same patient start exhibiting different morphological characteristics so as to disguise their bad intentions. This “tumor cell heterogeneity” makes glioblastoma hard to treat, even with therapy.

During their study, the authors discovered that a protein called BRD8, which packages our genome when becomes highly active, causes glioblastoma. 

One of the study authors and a professor at CSHL, Alea A. Mills, told IE, “You can think of BRD8 as protein machinery that packages our genome, unfortunately, sometimes in a bad way. Too much of it makes glioblastoma—the most common adult cancer that starts in the brain—thrive. We discovered that we can shut down glioblastoma by turning off BRD8.”

BRD8 protein machinery affects the functioning of another protein called P53 (tumor protein 53), which actually works as a tumor-suppressing pathway in the human body. The authors describe BRD8 as the “Achilles heel” (soft spot or weakness) of glioblastoma and P53 as our body’s natural cancer-defense mechanism. 

Their study suggests that by targeting and shutting down BRD8, the unmutated P53 genes in patients can be reactivated. These tumor-suppressing genes will then stop tumor growth and eventually turn off glioblastoma in the patient’s body. 

This approach can work for most glioblastoma patients

Shutting down a mysterious gene can help patients get rid of the deadliest brain cancer
The inverse relationship between BRD8 and P53.

BRD8 causes glioblastoma in the human brain by binding a unique substrate (un-acetylated H2AZ) via a lock-and-key mechanism. The researchers argue that they can design small molecules to disrupt this interaction as a therapeutic strategy for treating patients with glioblastoma

They claim that targeting BRD8 this way is highly effective as long as P53 is still functional, which according to them, is the case in about 71 percent of glioblastoma cases (crossing all molecularly and clinically-defined subtypes). 

“Our findings suggest that therapeutic strategies targeting BRD8 could be used to treat the majority (~71 percent) of glioblastoma patients: those that have tumors in which P53 is unmutated,” Professor Mills told IE.

The current study is supported by significant human data, however, it will be important moving forward to survey additional tumor specimens from glioblastoma patients. Professor Mills and her team are working on this front by collaborating with neurooncological surgeons and pathologists who treat patients with this malignancy on a daily basis.

They are also trying to further understand the molecular details of the lock and key way that BRD8 employs to cripple P53 function and are developing small molecules that disrupt this interaction to reawaken the cancer-preventing power of P53. Hopefully, their efforts will make it possible to treat and cure glioblastoma effectively in the near future.

For more information on brain cancer and glioblastoma, you can also check out the following resources from the American Association of Neurological Surgeons, Cancer Research UK, Cancer Treatment Centers of America, and the National Cancer Institute.  

The study is published in the journal Nature.

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