New approach protects the brain from radiation-induced cognitive decline

While tremendous relief comes from successfully battling cancer, survivors can also experience cognitive impairments caused by the disease and its treatment. Up to 70% of survivors experience trouble with memory and concentration, negatively impacting their quality of life and independence.

What if we could somehow protect the brain from cancer-related cognitive impairment (CRCI)?

An experimental study by UC Irvine researchers paves the way. Conceptualized and led by Munjal Acharya, PhD, an associate professor in the Department of Anatomy & Neurobiology, the study addresses cranial (brain) radiation-induced cognitive decline.

"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," says Acharya. "This opens a realistic pathway to preserving quality of life for millions of brain cancer survivors currently facing this unmet medical need."

The findings are outlined in "C5aR1 Inhibition Alleviates Cranial Radiation-Induced Cognitive Decline," a research article published in Cancer Research, a flagship journal for the American Association for Cancer Research (AACR).

Protection through targeted inhibition

The researchers found that targeted inhibition of a specific immune response pathway in the brain protects memory and cognition from the neuro-inflammatory effects of radiation therapy for brain cancer.

"The pathway in question is the 'complement cascade,' and the target is blocking the signaling between complement protein C5a and its receptor, C5aR1," explains lab research assistant An Do. The team investigated a blockade of this signaling through two different approaches: genetically, using a transgenic mouse model to delete (knockout) the C5ar1 gene, and in a pharmacological model with the inhibitor drug PMX205.

"Both approaches were found to improve memory and cognitive performance of irradiated mice with and without brain cancer," added Robert Krattli Jr., a staff research associate in Acharya's laboratory. "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."

Using PMX205 to block C5aR1 is especially promising given that the drug is orally available, penetrates the brain and has already been proven safe in human trials. It is also currently under clinical trial in Australia led by Trent Woodruff, PhD (University of Queensland), for treating amyotrophic lateral sclerosis (ALS), with initial results showing no side effects, toxicities or adverse reactions. Woodruff worked on the study with the UC Irvine team.

Next steps: From bench to bedside

The next steps involve testing the C5aR1 inhibitor PMX205 in more clinically relevant brain cancer models and radiation therapy regimens.

"We plan to study PMX205 prophylactically and in combination with radiation and chemotherapy, like temozolomide, using genetically engineered mouse models and patient-derived xenografts," says Acharya. These experiments will better mimic clinical settings, including fractionated radiation doses typically used in patients. "These steps aim to translate the promising neuroprotective effects seen in mice into therapies for human brain cancer survivors at risk of cognitive decline."

By personalizing treatment using C5aR1 inhibitors like PMX205, patients can receive protection tailored to their risk of cognitive decline while undergoing brain cancer therapy. A similar pre-clinical approach for Alzheimer's disease is being led by Acharya's collaborator, Andrea Tenner, PhD, who also contributed to the study.

"This approach allows for precise intervention to prevent unwanted side effects without altering the effectiveness of tumor treatment," says Acharya. "The ability to use a safe, brain-penetrant drug already tested in humans demonstrates how targeted molecular therapies can improve outcomes and quality of life for cancer survivors through precision medicine."