A new study offers hope for brain cancer patients facing memory loss from radiotherapy. By blocking a single immune receptor, scientists preserved cognition in mice without dulling the cancer-killing power of radiation.
Radiotherapy is essential for treating many brain cancers, but it often causes long-term cognitive problems, such as memory decline, decreased attention, and difficulties with problem-solving. For survivors, it’s a cruel tradeoff – beating cancer only to face lasting cognitive decline.
A new study by researchers from the University of California Irvine (UCI) and the University of Queensland has focused on C5aR1, a receptor that’s involved in the damaging neuroinflammation triggered by radiotherapy.
“We’ve identified a new, targeted way to protect the brain from the harmful side effects of cranial radiation therapy, a standard of care for brain cancers that often causes irreversible cognitive decline,” said Munjal Acharya, PhD, the study’s corresponding author and an associate professor in UCI’s Department of Anatomy and Neurobiology. “This opens a realistic pathway to preserving quality of life for millions of brain cancer survivors currently facing this unmet medical need.”
The radiation-induced brain injury comes largely from inflammation triggered by the brain’s complement system, a group of about 30 proteins that circulate in your blood and tissues. They “complement” or help the rest of the immune system – especially antibodies and white blood cells – by detecting, tagging, and destroying harmful invaders. If the complement system is overactive, it can damage healthy tissues, including the synapses or connections between neurons.
“The pathway in question is the ‘complement cascade,’ and the target is blocking the signaling between complement protein C5a and its receptor C5aR1,” said co-author An Do, a professor in the Department of Neurology at UCI.
The researchers used two main strategies in mice. One, genetic knockout: mice were bred without the C5aR1 gene. And two, drug treatment: normal mice were given PMX205, a small molecule that blocks C5aR1 and can cross the blood-brain barrier. It was administered for a month via subcutaneous injection and drinking water.
They tested both healthy mice and mice implanted with brain tumors (glioblastoma and astrocytoma cell lines). All received 9 Gy of cranial radiation, equivalent to a strong therapeutic dose. The researchers then ran behavioral tests, including object recognition and location memory tasks, and a fear-memory extinction test, to measure learning, memory, and cognitive flexibility. They also examined brain tissue for signs of microglial activation (immune cell overreaction), astrogliosis (swelling of support cells), loss of synapses, and inflammatory gene expression.
Radiation caused major cognitive decline in the untreated mice. Both C5aR1 knockout and PMX205-treated mice maintained normal learning and memory performance, showing that blocking this receptor prevented radiation-induced cognitive impairment. Radiation normally triggered inflammation and activation of brain immune cells, microglia and astrocytes. Mice lacking C5aR1 or treated with PMX205 had much lower inflammation, as seen in reduced markers. There were also indicators of damaged neural connections in untreated mice. C5aR1-blocked or knocked mice, however, retained normal synaptic protein levels, meaning their brain wiring was intact.
Importantly, PMX205 didn’t interfere with radiotherapy’s anti-tumor effects. Tumor size and survival outcomes were as good – and in some cases better – than with radiation alone. Treated tumor-bearing mice also retained cognitive ability, suggesting this approach can protect the brain without protecting the cancer. Blocking C5aR1 shifted the genetic profile of irradiated brains away from inflammation. Genes related to neuroprotection, synaptic plasticity, and reduced DNA damage were upregulated, while pro-inflammatory genes were downregulated.
“Both approaches were found to improve memory and cognitive performance of irradiated mice with and without brain cancer,” said Robert Krattli, the lead author of the study and a staff research associate in Acharya’s lab. “Importantly, neither the gene knockout nor the drug treatment impeded the cancer-killing ability of radiation therapy, so our approach protected the brain without compromising the efficiency of radiation therapy against cancer.”
The study has limitations. The researchers used a single high radiation dose, whereas human treatments are usually fractionated – that is, given in smaller doses over time. Future work must confirm if C5aR1 inhibition still protects under clinical dosing schedules. The research was conducted in mice, so translation to humans requires caution. Long-term effects and potential drug interactions with standard therapies still need testing. Cognitive testing in mice has limits; it captures some but not all aspects of human cognition.
Interestingly, the researchers may already be a couple of steps ahead in the process. PMX205, the tested drug, has already passed early human safety trials in healthy adults and amyotrophic lateral sclerosis (ALS) patients, showing no major side effects or infections. If further validated, C5aR1 inhibitors could become an add-on therapy for brain cancer patients undergoing radiation therapy.
“We plan to study PMX205 prophylactically and in combination with radiation and chemotherapy, like [the drug] temozolomide, using genetically engineered mouse models and patient-derived xenografts,” Acharya said. “These steps aim to translate the promising neuroprotective effects seen in mice into therapies for human brain cancer survivors at risk of cognitive decline.”
The study was published in the journal Cancer Research.
Source: UC Irvine School of Medicine
