Brain Cancer’s ‘immortality Switch’ Turned Off With Crispr

May 1, 2019

Many cancer cells can divide indefinitely by turning on a “perpetual switch,” a trick that most other cell types can’t perform. Now, researchers have found a way to short-circuit that switch, which could slow or stop the spread of more than 50 types of cancer, including the kind of brain cancer that Senator John McCain died of last month.

In the new study, researchers examined glioblastoma brain cancer cells removed from cancer patients and found that tiny fragments of a common protein called GABP were key to enabling the cancer cells to activate the so-called perpetual switch. When the researchers removed the protein segment, the cancer cells – both in a laboratory dish and when transplanted into mice – stopped their voracious multiplication and behaved like human leonine cells.

The researchers, led by UCSF neurosurgery professor and neuro-oncologist Joseph Costello, said they hope to develop a drug that would inhibit only that small segment of GABP, depriving cancer cells of the key to the switch while avoiding harming other cells. (Costello disclosed in the study that he and a co-author are the founders of Telo Therapeutics, which is working with pharmaceutical company GlaxoSmithKline to find a small molecule with drug potential.)

The findings were published today (Sept. 10) in the journal Cancer Cell.

The uncontrolled split
One characteristic of cancer cells is their ability to divide uncontrollably. Almost all other cells can only divide a certain number of times before they die. The major exceptions are stem cells, which can divide continuously throughout the life of the organism to replenish all those other cells that are dying, such as blood and skin cells.

The lifespan of a cell is set by structures called telomeres, which cover the ends of chromosomes, like the hoops on a shoelace. Each time a cell divides, the telomeres get a little shorter until, eventually, they are too short to protect the integrity of the chromosomes. At that point, cell division stops.

Stem cells escape this death by using telomerase, an enzyme that rebuilds telomeres. Indirectly, many cancer cells do the same thing, by using a mutation in a gene called TERT, short for telomerase reverse transcriptase. Cancer cells that can turn on this gene can divide indefinitely, just like stem cells.

Scientists have been understanding cancer’s use of the perpetual switch for years. Previous studies have found that more than 90 percent of tumors have mutations that allow the growing tumor to turn on the expression of TERT and produce telomerase. But cancer drugs that block telomerase alone have proven too toxic for patients because they also choke off stem cells, limiting their ability to produce new blood cells and other important cells.

Costello’s research team focused on glioblastoma, the most aggressive form of brain cancer, and found a way to restrict the cancer cells’ access to the perpetual switch only, without affecting the stem cells. Specifically, the researchers found that the cancer cells were using a part of the GABP protein, GABPbeta1L, to activate the switch.

The GABP protein is used by many types of cells for a variety of tasks, so completely inhibiting the protein could have adverse effects on the entire body. Researchers turned to trying to remove only the GABPbeta1L element, using the gene-editing tool CRISPR.

And it worked. According to experiments done by the researchers in laboratory dishes and mice, GABP proteins lacking beta1L had a detrimental effect on cancer cells, but not on other cells.

“These findings suggest that the beta1L subunit is a promising new drug target for the treatment of aggressive glioblastoma, and potentially many other cancers with TERT promoter mutations,” Costello said in a press statement.

Glioblastoma target?
Both McCain and Beau Biden, son of former Vice President Joe Biden, died of glioblastoma. While it’s not publicly known if their form of glioblastoma had a TERT promoter mutation, Costello told Live Science that it’s likely, given that an estimated 83 percent of glioblastomas have the mutation.

Dr. John Laterra, co-director of the brain cancer program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, who was not involved in the study, said the findings are “of high potential significance given the known role of TERT in driving cancer cell immortality and glioma malignancy.

“These findings provide a compelling argument for future work aimed at identifying [molecules] that inhibit the ability of GABPbeta1L or other regulators” of GAPB to activate the immortality switch, Laterra told Live Science.

He added that it would be important to replicate this experiment in other tumor models, preferably those that come directly from patient samples. In addition, while cancer cells that already lack GABPbeta1L grow less aggressively when transplanted into mice, more work needs to be done in mice, Laterra said. He said the researchers need to design an experiment to determine if they can block or remove GABPbeta1L to stop cancers already developing in the mice.

Costello said his group and other collaborators will pursue two approaches simultaneously: creating a small-molecule drug that targets GABPbeta1L, and developing a CRISPR-based therapy that alters human genes so they don’t produce GABPbeta1L. the CRISPR approach is directed at human brain cancer cells transplanted into mice in this experiment . The researchers are working with GSK on a previous project. But both methods are highly experimental and will take several years to develop, Costello told Live Science.