Jan. 20, 2018
Mayo Clinic's Center for Regenerative Medicine is developing a neuro-oncology service line to optimize quality of life for patients treated for brain tumors. Although recent improvements in cancer therapies might lengthen life spans, survivors often must live with the cognitive sequelae of radiation-induced brain injury. Mayo Clinic's goal is to develop regenerative strategies to mitigate those effects in patients with low-grade gliomas or other tumors who can expect to live for decades after treatment.
Transplantation of new healthy OPCs into the radiated brain
Radiation causes many changes in the brain, some of which are illustrated here, including microglial activation, damage to oligodendrocytes and loss of oligodendrocyte progenitor cells (OPCs). By transplanting new healthy OPCs into the radiated brain, the OPC population is replenished, and these cells can migrate throughout the brain to replace damaged oligodendrocytes, enabling neuronal axons to be remyelinated. In this way, cognitive deficits induced by radiation can be reversed. This process has so far been demonstrated in animal models. Future studies must assess if the strategy is effective in human patients.
One potential strategy involves oligodendrocyte progenitor cells (OPCs). Radiation renders OPCs dysfunctional, impeding their reparative response. The resulting white matter degeneration is a major contributor to radiation-induced cognitive impairment after brain cancer treatment. However, preclinical research has shown that healthy, functioning exogenous OPCs maintain their normal function upon implantation into a previously irradiated brain — migrating widely, generating oligodendrocytes and remyelinating lesioned areas.
"In our lab we have seen that the irradiated brain is quite changed in some way that promotes the migration of these oligodendrocyte progenitor cells into the brain. I think that has tremendous potential," says Terence (Terry) C. Burns, M.D., Ph.D., a consultant in Neurosurgery at Mayo Clinic in Rochester, Minnesota, and principal investigator in Mayo Clinic's Regenerative Neurosurgery and Neuro-Oncology Laboratory.
In his clinical practice Dr. Burns sees patients whose low-grade gliomas were irradiated more than a decade earlier. "The patient might be only 50-something years old but is walking like an 80-year-old, and has symptoms of dementia," Dr. Burns says. "Fortunately, the tumor has been held at bay for many years. But at what cost?"
In a study published in the May 2015 issue of Glia, Dr. Burns and colleagues demonstrated that the transcriptional profile of radiated microglia closely mirrors that acquired by microglia during aging. "The white matter also atrophies and loses volume," he says. "Our studies suggest that brain radiation may accelerate aging-like changes in the brain. It's as though aging is happening in fast forward in the brain. We are now trying to minimize the amount of brain exposed to radiation, and come up with strategies to help rejuvenate the radiated brain."
In an article published in the May 2016 issue of Neurosurgical Focus, Dr. Burns noted that studies using animal models of acute demyelination, including toxin-induced demyelination, have shown that OPCs generate new oligodendrocytes to swiftly remyelinate a lesioned area, averting permanent axonal injury. Of particular interest are preclinical studies suggesting that OPCs implanted in the forebrains of radiated animal models improve cognitive function, and OPCs implanted in the hindbrains improve motor function.
Exogenous OPCs are being explored for use in clinical trials of childhood leukodystrophies, multiple sclerosis and Huntington's disease. "At this point, the most promising source of the cells may be from embryonic or induced pluripotent stem cells, so it is essential to determine early if there are any safety concerns, " Dr. Burns says.
"There are a lot of questions to be answered, but what we have seen so far suggests OPCs as a promising avenue for treating radiation-induced brain injury," he adds. "Nevertheless, we're not focusing exclusively on OPCs. Unlike other forms of brain injury — for example, traumatic brain injury, stroke and Alzheimer's disease — radiation-induced brain injury allows us to intervene possibly even before the damage occurs. There are several promising neuroprotective strategies that appear to work best if administered prior to injury. This is a problem I'm optimistic we can solve."
Tracking cognitive function in patients with glioma
At Mayo Clinic, low-grade gliomas are an initial target for neuro-oncology regenerative medicine. Currently, patients with these tumors can expect to live for approximately 15 years after treatment. "We're making rapid progress, so I am hopeful in 15 years, we'll actually have much more effective treatments," Dr. Burns says. "For now, we need to buy time for patients and do our best to preserve their quality of life."
Before treating patients with low-grade gliomas, Dr. Burns schedules neuropsychological assessments, which are repeated after surgery and periodically after chemotherapy and radiation. "Cognitive outcomes are often ignored in cancer treatment, but I feel we need to be systematic about compiling and analyzing these data," he says. "How much worse is cognitive function after treatment, and in which domains? We believe the hippocampus is particularly sensitive to radiation, based on memory performance, but impairments in executive function and multitasking may reflect injury to other white matter tracts.
"What about the contralateral cingulate gyrus? We need the integrated data to determine when and how best to use the tools we have of surgery, radiation and chemotherapy, to maximize benefit and minimize cognitive impacts."
Children are another patient population severely affected by radiation-induced brain injury. Survivors of childhood medulloblastoma can experience an IQ loss of as much as 25 points, due to the long-term effects of radiation treatment. "Children could have the most to gain from our regenerative strategies, since their brains are still developing and the demyelinating impacts of radiation can worsen over time," Dr. Burns says.
"In the brain tumor field, we've not devoted enough attention to cognitive performance and quality of life because the enemy has been the tumor," he adds. "The regenerative neuro-oncology service line initiative at Mayo Clinic will help ensure we not only get rid of the tumor but translate regenerative strategies to patients to preserve and optimize brain performance despite the tumor."
For more information
Li MD, et al. Aging-like changes in the transcriptome of irradiated microglia. Glia. 2015;63:754.
Burns TC, et al. Radiation-induced brain injury: Low-hanging fruit for neuroregeneration. Neurosurgical Focus. 2016;40:E3.