This gene mutation is key to glioblastoma’s ‘immortality’ and could point to drug targets

lioblastoma, the brain cancer that took the life of Sen. John McCain, has proven especially difficult to target with drugs. Now researchers at the University of California, San Francisco, believe they’ve discovered how a common cancer mutation drives glioblastoma—a finding that could inspire new targets for drug treatments, they say.

The mutation, which occurs in a gene regulator called TERT and is the most common mutation in glioblastoma, gives cancer cells "immortality," or the ability to divide and spread indefinitely. By studying cells from glioblastoma patients, the UCSF researchers discovered that a particular form of a protein called GABP drives TERT promoter mutations. They published their observations in the journal Cancer Cell.

It was a particular subunit of the protein called GABP-ß1L that seemed to activate the mutant promoters, the researchers discovered. That subunit is a potential drug target that’s now being further investigated by UCSF spinoff Telo Therapeutics, in partnership with GlaxoSmithKline, according to a press release.

TERT is important because it’s one of two genes that encode telomerase, an enzyme that gives stem cells the ability to divide indefinitely. Most normal cells have limited lifespans, but many human cancers have activated telomerase because of TERT mutations. Hence their ability to spread and become deadly.

Targeting telomerase with drugs has proven challenging because of off-target effects on normal blood stem cells. The UCSF team believed a safer route would be to go after TERT promoters instead.

"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," said senior author Joseph Costello, Ph.D., a UCSF neuro-oncology researcher and co-founder of Telo, in the statement.

Costello’s team used different techniques, including CRISPR gene editing, to eliminate GABP-ß1L from glioblastoma cells. When they did that, the growth of the cells slowed dramatically, they reported. Then they tried implanting both edited and unedited cells into mice. The unedited cells grew aggressively, eventually proving fatal, while the edited cells grew slowly and were less lethal. Because they were not targeting TERT itself, they believe a drug that inhibits GABP-ß1L would be unlikely to interfere with normal cell processes.

The search for effective treatments for glioblastoma has left a long string of failures. Most recently, VBL Therapeutics announced disappointing clinical trial results earlier this year for its combo treatment designed to cut off the blood supply to tumors.

Still, there is plenty of investor interest in startups pursuing new ideas in glioblastoma. Istari Oncology, a Duke spinoff, has raised about $5 million to advance its immuno-oncology approach to glioblastoma, which involves an engineered form of poliovirus. And Quentis raised $48 million earlier this year to pursue therapies that modulate endoplasmic reticulum stress response pathways, which are associated with poor outcomes in many cancers, including glioblastoma.

Costello and his colleagues at UCSF are working in partnership with GSK to find small molecules to target GABP-ß1L. Although their priority is glioblastoma, they believe their approach could ultimately be applied to many tumor types, as more than 50 human cancers have been linked to mutations in TERT promoters.

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