Groundbreaking step toward protecting the brain during radiation therapy
Radiation therapy remains a cornerstone in treating brain cancers, but its cognitive side effects can shadow the relief of cancer remission. Up to 70% of survivors report challenges with memory, attention, and executive function, profoundly affecting daily life and independence. A new study from UC Irvine offers a targeted strategy to shield the brain from these cognitive costs without diminishing the tumor-killing power of radiation.
Targeted immune signaling in the brain as a safeguard
Led by Munjal Acharya, Ph.D., the UC Irvine team focused on a specific brain immune pathway known as the complement cascade. They found that blocking the signal between the complement protein C5a and its receptor C5aR1 can prevent the neuroinflammation that drives cognitive decline after cranial irradiation.
As lab researcher An Do notes, this approach aims to interrupt a harmful chain of events in the brain, rather than altering the effectiveness of radiation against cancer. The researchers demonstrated that inhibiting C5aR1 preserves memory and cognitive performance in irradiated mice, both with and without brain tumors.
Two complementary methods strengthen the finding
The study employed two parallel strategies to shut down C5aR1 signaling. In a genetic model, the C5ar1 gene was knocked out in mice. In a pharmacological model, researchers used PMX205, a brain-penetrant inhibitor already explored in human trials for other conditions. In both cases, cognitive outcomes improved after radiation without compromising tumor control.
Robert Krattli Jr. emphasizes that the cancer-killing efficacy of radiation remained intact in treated animals. This crucial point suggests a feasible path to protect patients’ brains without reducing the therapy’s ability to eradicate cancer cells.
PMX205: a clinically promising tool
PMX205 stands out because it is orally available and can cross the blood-brain barrier. Its safety profile in early human trials is encouraging, and ongoing work in ALS trials in Australia is exploring similar biological targets without adverse effects. The convergence of safety, brain access, and efficacy in improving cognitive outcomes makes PMX205 a compelling candidate for further clinical development in brain cancer patients.
From bench to bedside: planning the next clinical-relevant studies
To move closer to patient care, Acharya and colleagues are planning preclinical studies that more accurately reflect human brain cancer treatment. They will test PMX205 in models that mimic standard clinical regimens, including fractionated radiation doses and combination therapy with chemotherapy such as temozolomide. They will use genetically engineered mouse models and patient-derived xenografts to capture the heterogeneity of human tumors and treatment responses.
The ultimate goal is precision medicine: tailor a protective strategy to a patient’s cognitive decline risk while preserving the tumor-killing power of radiotherapy. Acharya envisions a future where C5aR1 inhibitors are deployed alongside brain cancer treatment to safeguard memory and thinking, dramatically improving survivors’ quality of life.
Broader implications and next steps
While the immediate application targets brain cancer patients undergoing cranial irradiation, the same principle—modulating a specific immune pathway to prevent collateral brain injury—could influence other neurologic conditions aggravated by treatment. The collaboration with Andrea Tenner, Ph.D., highlights a broader interest in leveraging precise immune modulation to reduce cognitive side effects across diseases.
Why this research matters
This study does not alter how radiation kills tumors. Instead, it adds a protective layer that could preserve the brain’s cognitive functions, addressing a major unmet need for brain cancer survivors. By using a drug with human safety data and a clear mechanism, the path to clinical trials is clearer, bringing hope for personalized neuroprotection during cancer therapy.
