What makes aggressive brain cancer 'immortal?'

A new study has discovered what makes glioblastoma cells so resilient and difficult to destroy. The finding may lead to more effective, targeted treatments in the future, the researchers argue.

Scientists from the University of California, San Francisco have recently investigated why a very aggressive and often treatment-resistant type of brain cancer, called glioblastoma, is "immortal."

They explain that it all starts with a mutation in TERT promoters, which influence when the TERT gene is activated.

TERT is one of the genes that encode the telomerase complex.

The activity of telomerase, a specialized protein, is important when it comes to regulating the length of telomeres. These are structures that "cap" the ends of chromosomes, or molecules found in the nuclei of most cells, which carry genetic information.

Telomeres' role is to stop DNA material contained in the chromosomes from unraveling. However, every time a cell divides, telomeres will become shorter and shorter until they are no longer functional. This also determines the end of a cell's life.

Telomerase works by prolonging telomeres, thus ensuring the continued life of a cell. Yet normally, telomerase is active in very few cells; usually the stem cells of human embryos, thereby allowing them to continue to grow and develop in the womb.

The scientists explain that the cells of many types of cancer are able to imitate the mechanism of stem cells thanks to mutations in the TERT gene, which allows them to continue living for an indeterminate period of time.

However, they also add that recent studies have pointed out that over 50 types of cancer may access "immortality" not through mutations of the TERT gene, but through mutations of TERT promoters — and glioblastoma is one of them.

An intricate mechanism for survival

In their new study — the findings of which now appear in the journal Cancer Cell — the researchers observed that TERT promoter mutations in glioblastoma depend on the existence of a specific component of the GABP protein, a type of protein that plays a key role in cell functioning.

Working with cells derived from human glioblastoma, senior study author Joseph Costello and his team identified one peculiarity: the GABP protein that activates the mutated TERT promoters in brain cancer features a subunit called GABP-ß1L.

Costello and colleagues found that if they removed GABP-ß1L from tumor cells using advanced gene editing techniques and transplanted them into mice, it slowed tumor growth significantly. At the same time, when GABP-ß1L was removed from healthy cells in rodents, this did not appear to affect their normal functioning.

"These findings," explains Costello, "suggest that the ß1L subunit is a promising new drug target for aggressive glioblastoma and potentially the many other cancers with TERT promoter mutations."

The scientists also noted that the mutations seen in the TERT promoter in glioblastoma allow GABP to bind to the promoter and therefore activate it. However, they add that nothing like this ever happens in healthy cells. "This was really intriguing to us," says Costello, adding:

"You can't create a drug to target a promoter itself, but if we could identify how GABP was binding to the mutated promoter in these cancers, we might have a remarkably powerful new drug target."

In the future, the team aims to develop a type of drug that will be able to remove GABP-ß1L in a similar way as gene editing, so as to slow down the progression of normally aggressive tumors.

"In theory what we have now is a therapeutic target that is not TERT itself, but a key to the TERT switch that is not essential in normal cells. Now we have to design a therapeutic molecule that would do the same thing," Costello notes.

He and his colleagues are currently conducting research pursuing this therapeutic target in the laboratories of a company founded by the senior scientist. For this, they have partnered with GlaxoSmithKline, a pharmaceutical company.