Overview: A New Strategy to Shield the Brain During Radiation
Cancer survivors often face cognitive challenges after treatment. In brain cancer, cranial radiation therapy is a standard lifesaving intervention, but it can cause lasting problems with memory, attention, and executive function. A recent experimental study from the University of California, Irvine, led by Munjal Acharya, Ph.D., unveils a targeted approach that could protect the brain from these cognitive side effects while preserving the tumor-killing power of radiation.
The team reports their findings in Cancer Research, in a paper titled “C5aR1 Inhibition Alleviates Cranial Radiation-Induced Cognitive Decline.” Their work highlights a specific immune signaling pathway in the brain and demonstrates how blocking it can mitigate neuroinflammation and preserve cognition.
Targeting the Complement Cascade to Preserve Cognition
Damage to brain tissue during radiation is partly driven by neuroinflammation. The UC Irvine researchers focused on the complement cascade, a part of the immune system that, when activated in the brain, can contribute to cognitive decline. They found that blocking the interaction between the complement protein C5a and its receptor C5aR1 offers a protective effect for memory and learning in irradiated mice.
According to lab research assistant An Do, the dual approach—genetic deletion of the C5ar1 gene and pharmacological blockade using an inhibitor drug—both yielded improved cognitive performance after cranial irradiation. “Both approaches improved memory and cognition in irradiated mice with and without brain cancer,” noted Robert Krattli Jr., a staff research associate in Acharya’s lab.
Two complementary models show promise
The study used a transgenic mouse model with C5ar1 knockout to demonstrate the impact of removing the C5aR1 receptor. In parallel, researchers used PMX205, an inhibitor that can cross the blood-brain barrier and block C5aR1 signaling. In both scenarios, the animals showed better performance on memory tasks after radiation, with no compromise to the cancer-control effects of the radiation therapy itself.
A key finding was that PMX205 is orally available and brain-penetrant, characteristics that make it a particularly attractive candidate for clinical translation. The drug has already undergone safety testing in humans and is currently in trials for amyotrophic lateral sclerosis (ALS) in Australia, led by Dr. Trent Woodruff. Importantly, early results indicate no adverse effects, supporting a favorable risk-benefit profile for further study in brain cancer patients.
From Bench to Bedside: What Comes Next
Acharya emphasizes that the next phase involves more clinically relevant brain cancer models and radiation regimens. The team plans to test PMX205 both prophylactically and in combination with standard treatments like temozolomide, across mouse models that mimic patient tumors and radiotherapy protocols. This includes fractionated radiation, which mirrors how clinicians deliver therapy in the clinic.
“Our goal is to translate these neuroprotective effects into a precision medicine approach that protects patients’ cognitive function without dampening the therapeutic impact on the tumor,” Acharya states. The research also aligns with similar preclinical efforts to address cognitive decline in other brain disorders, including collaboration with Andrea Tenner, Ph.D., on related projects.
Implications for Brain Cancer Survivors
If successful in humans, a C5aR1 inhibitor like PMX205 could become part of personalized treatment plans for brain cancer patients at high risk of CRCI (cancer-related cognitive impairment). Clinicians could tailor protective strategies to an individual’s risk profile, offering a way to maintain quality of life during and after cancer therapy. The approach exemplifies precision medicine: target a specific immune pathway to shield healthy brain tissue while keeping the cancer-killing effects of radiation intact.
Why This Research Matters
Beyond the immediate goal of protecting cognition, this work illustrates how targeted molecular therapies can prevent side effects without sacrificing efficacy. The use of an already human-tested, brain-penetrant drug accelerates the potential for clinical trials in brain cancer survivors. As the field advances, patients could benefit from treatments that reduce long-term cognitive burdens and preserve independence after therapy.
In sum, the UC Irvine study offers a beacon of hope: by interrupting the C5a–C5aR1 signaling axis, it may be possible to reduce cranial radiation-induced cognitive decline, supporting better long-term outcomes for millions of brain cancer survivors.
