New research offers a targeted safeguard for brain cancer patients undergoing radiation therapy
For many cancer survivors, the battle isn’t over once tumors are treated. Cognitive challenges—trouble with memory, attention, and concentration—can persist after cranial radiation therapy. In brain cancer patients, up to 70% report some form of cognitive impairment, a burden that affects independence and quality of life. A new line of investigation from the University of California, Irvine, points to a practical way to shield the brain from these side effects without compromising the power of cancer treatment.
Targeting a brain immune pathway to prevent neuroinflammation
The UC Irvine team, led by Munjal Acharya, Ph.D., explored how the brain’s immune responses contribute to cognitive decline after radiation. They identified the complement cascade—an immune signaling pathway—as a key mediator of radiation-induced neuroinflammation and its cognitive consequences. In particular, signaling through the interaction of the complement protein C5a and its receptor C5aR1 was implicated as a driver of brain dysfunction following cranial irradiation.
Two complementary approaches show promise
Researchers tested blocking C5aR1 using two strategies in mouse models: genetic deletion of the C5ar1 gene and pharmacological inhibition with PMX205, a brain-penetrant drug. In both cases, irradiated mice demonstrated improved memory and cognitive performance compared with controls. Importantly, the protective effect did not compromise the cancer-killing ability of radiation therapy in the models, addressing a major concern about combining neuroprotection with tumor control.
Why this matters for patients
The dual findings—effectiveness in preserving cognition and non-interference with tumor treatment—suggest a feasible path toward incorporating C5aR1 inhibitors into brain cancer care. PMX205 is particularly encouraging because it is orally administered and capable of crossing the blood-brain barrier. Furthermore, PMX205 has already been studied in humans for other indications and is currently in clinical trials for ALS in Australia, with early safety data appearing favorable. This existing safety profile accelerates the potential translation from bench to bedside.
From preclinical success to clinical reality
Looking ahead, Acharya and colleagues plan to test PMX205 in more clinically relevant models that better mimic patient treatments. They will explore prophylactic use and combination regimens that pair radiation with chemotherapy, such as temozolomide, in genetically engineered mice and patient-derived models. These studies aim to reflect real-world treatment protocols, including fractionated radiation doses, to determine how best to protect cognition without dampening anti-cancer efficacy.
Personalized precision medicine for cognitive protection
The team envisions a future where C5aR1 inhibitors are tailored to individual risk profiles. By identifying patients at higher risk of CRCI, clinicians could selectively apply brain-protective strategies during cranial radiation, preserving memory and attention while maintaining robust tumor control. Collaboration with experts in neurodegenerative disease, including researchers exploring Alzheimer’s genetics and inflammation, reinforces the broader relevance of targeted immune modulation for brain health.
Availability and next steps
While more work remains before C5aR1 inhibitors become standard care, the current study lays a robust groundwork. The approach demonstrates that precise molecular therapies can mitigate side effects of cancer treatment without sacrificing effectiveness against tumors. As precision medicine advances, protecting cognitive function could become a routine companion to successful cancer therapy.
