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Many cancer cells can divide indefinitely by operating an "immortality switch," a trick that most other types of cells can not achieve. Now researchers have found a way to bypass this change, which could slow or stop the spread of more than 50 types of cancer, including the type of brain cancer that Senator John McCain died last month.
In the new study, researchers examined brain glioblastoma cancer cells that had been removed in cancer patients, discovering that a small segment of a common protein called GABP was the key to allowing cancer cells to develop. Activate the switch says immortality. When the researchers removed this protein segment, the cancer cells – both in the lab boxes and during transplantation in the mice – stopped their voracious multiplication and behaved like mere deadly cells. [10 Do’s and Don’ts to Reduce Your Risk of Cancer]
The researchers, led by Joseph Costello, a professor of neurosurgery and expert in neuro-oncology at the University of California at San Francisco, said they hoped to develop a drug that could inhibit this tiny segment of GABP, depriving cells cancerous of their key. at the switch while avoiding harming other cells. (Costello revealed in the study that he and a co-author are the founders of Telo Therapeutics, which works in partnership with the pharmaceutical company GlaxoSmithKline to research small molecules potentially useful as drugs.)
The results were published today (Sept. 10) in the journal Cancer Cell.
Uncontrolled division
A signature of cancer cells is their ability to divide without control. Almost all other cells can only divide a few times before they die. The main exceptions are stem cells, which can divide throughout the life of an organism to replenish all other cells that are dying, such as blood and skin cells.
The cell lifespan is defined by structures called telomeres, which cover the ends of chromosomes and serve as aglets on a lace. With each cell division, the telomeres become a little shorter, until they end up being too short to protect the integrity of the chromosomes. It is at this point that cell division stops.
Stem cells escape this mortality by using telomerase, an enzyme that reconstructs the telomere. Indirectly, many cancer cells do the same thing by exploiting mutations in a gene called TERT, an abbreviation for telomerase reverse transcriptase. Cancer cells that can activate this gene can, like stem cells, divide indefinitely.
Scientists have understood the use of immortality change by cancer for years. Previous research has shown that more than 90% of tumors have mutations that allow growths to activate TERT expression and produce telomerase. But anti-cancer drugs that simply block telomerase have been shown to be too toxic for patients because the drugs also choke the stem cells, limiting the patient's ability to produce new blood cells and other vital cells.
By focusing on glioblastoma, the most aggressive form of brain cancer, the Costello group has discovered a way to limit access to the immortality switch only for cancerous, sparing cells. Specifically, the researchers found that the cancer cells were using part of the GABP protein, called GABPbeta1L, to activate the switch.
GABP protein is used by many types of cells for a multitude of tasks. The total inhibition of this protein would therefore have adverse effects on the whole body. The researchers instead tried to delete only the element GABPbeta1L, using the CRISPR gene editing tool to do it.
And it worked. GABP protein lacking beta-1L had a detrimental effect on cancer cells, but no effect on other cells, according to experiments conducted by researchers on laboratory dishes and in mice.
"These results suggest that the beta1L subunit is a promising new target for aggressive glioblastoma and potentially for many other cancers with TERT promoter mutations," Costello said in a press release.
Target of glioblastoma?
McCain and the son of former vice president Joe Biden, Beau Biden, both died of glioblastoma. Although it is not known publicly whether their form of glioblastoma has mutations of the TERT promoter, Costello said that it was likely that 83% of glioblastomas had such mutations. [5 Facts About Brain Cancer]
Dr. John Laterra, co-head of the brain cancer research program at Johns Hopkins' Sidney Kimmel Cancer Center in Baltimore, said the findings "are very important given the known role of TERT in driving immortality of cancer cells and malignancy of gliomas.
"The results provide a compelling argument for future work to identify [molecules] that inhibit GABPbeta1L or other regulators of "GAPB's ability to activate the immortality switch," Laterra told Live Science.
He added that it would be important to replicate this experience in other tumor models, preferably those derived directly from patient samples. In addition, although cancer cells already deficient in GABPbeta1L have developed less aggressively after transplantation in mice, additional work in mice is required, Laterra said. Researchers must design an experiment to determine if the cancer that has already developed in mice can be stopped by blocking or eliminating GABPbeta1L, he said.
Mr Costello said his group and other collaborators would pursue two parallel approaches: the creation of a small molecule drug targeting GABPbeta1L and the development of a CRISPR-based therapy capable of modifying human genes for that they do not produce GABPbeta1L. The CRISPR approach was performed for transplanted human brain cancer cells in mice in this experiment. The researchers are working with GSK on the previous project. Both approaches are very experimental, however, and it will take several years to develop them, Costello told Live Science.
Follow Christopher Wanjek @wanjek for daily tweets about health and science with a humorous side. Wanjek is the author of "Food at Work" and "Bad Medicine". His chronicle, Bad Medicine, appears regularly on Live Science.
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