Radiation that at first is beneficial later causes cells to senesce, promoting brain cancer’s return.
It’s a medical conundrum. Ionizing radiation, which at first extends the survival of glioblastoma patients after surgery, may later, ironically, help drive the brain cancer’s aggressive, untreatable recurrence.
Radiation therapy after surgery is the primary treatment for most glioblastoma patients. “Ionizing radiation works quite effectively, up to a point,” said Sandeep Burma, PhD, professor of neurosurgery and biochemistry and structural biology at The University of Texas Health Science Center at San Antonio. “Surgical resection of the tumor improves survival by approximately six months. Adding ionizing radiation extends survival to a year or even more. Unfortunately, the tumors always recur, and once they do, they are generally not responsive to therapy.”
Dr. Burma and a team of investigators at the Health Science Center’s Mays Cancer Center, home to UT Health San Antonio MD Anderson Cancer Center, are studying companion treatments to see if any can eliminate this Jekyll and Hyde property of ionizing radiation.
The team’s research, published in the journal Cancer Research, is intriguing. The scientists irradiated the brains of a group of healthy mice. A second control group of mice underwent mock irradiation. Thirty days later, the scientists implanted glioblastoma cells into the brains of the control and experimental mice. The implanted glioblastoma cells in the irradiated brains “grew like gangbusters,” Dr. Burma said.
Tumors in the irradiated brain were more invasive and lethal than those in the animals not treated with radiation, the team found.
“This is presumably because the brain microenvironment was changed by radiation,” Dr. Burma said. “We next carried out genetic and molecular analyses of the irradiated brain to find out what was changed. We figured out that radiation causes senescence in the brain, and the senescent cells seemed to be secreting a number of pro-tumor growth factors.”
What is senescence?
If a cell is old, stressed or damaged by insults such as radiation, it may enter a state in which it can no longer divide. This is senescence. Senescence normally serves as an anti-cancer barrier by preventing such damaged cells from proliferating. But during the last decade, it has become clear that the senescent cell can also be pro-cancer by spewing tumor-promoting factors.
“When we irradiate a brain tumor, normal cells like astrocytes in the vicinity of the tumor senesce and just sit there, spitting out growth factors that seem to drive tumor recurrence,” Dr. Burma said.
Radiation therapy of glioblastoma traditionally targets not only the tumor, but a two- to three-centimeter margin of normal brain tissue around it. This is done because glioblastoma cells are so infiltrative. Dr. Burma and his colleagues now believe that the irradiated margin of healthy brain cells becomes a fertile microenvironment for cancer regrowth. They will conduct further studies to understand this phenomenon.
Clearing out senescent cells
The team also administered agents to clear senescent cells in mice. This treatment, still in its infancy, is called senolytic therapy, and is being tested in Alzheimer’s disease, COVID-19 lung disease and a host of other disease conditions. “In our study, we showed that by using senolytics to clear senescent cells after radiation, we can slow down the growth of implanted tumor cells and improve survival,” Dr. Burma said. “We caution, however, that our mouse studies in this paper were not preclinical studies, because in a clinical setting, you would never treat with a therapy (radiation) first and then implant tumor cells later.”
Still, findings suggest that following radiation, adjuvant senolytic therapy could be a one-two punch against glioblastoma recurrence, Dr. Burma said.
“You come in with the first punch being radiation and with the second punch being a senolytic,” he said. “The idea is to remove the cells that have been rendered senescent by radiation and decrease their pro-cancer activity.”
Eventually, a radiation-senolytic combination could be an answer long sought by oncologists, families and patients alike to blunt glioblastoma recurrence. The research, supported by the National Institutes of Health and NASA, will continue. Stay tuned.
Elimination of Radiation-Induced Senescence in the Brain Tumor Microenvironment Attenuates Glioblastoma Recurrence
Eliot Fletcher-Sananikone, Suman Kanji, Nozomi Tomimatsu, Luis Fernando Macedo Di Cristofaro, Rahul K. Kollipara, Debabrata Saha, John R. Floyd, Patrick Sung, Robert Hromas, Terry C. Burns, Ralf Kittler, Amyn A. Habib, Bipasha Mukherjee and Sandeep Burma.
First published: Oct. 1, 2021, Cancer Research (published in print Dec. 1, 2021)