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Blocking C5aR1 Preserves Memory in Mouse Brain Radiotherapy Without Undermining Tumor Control

An oral, brain-penetrant candidate, PMX205, already shows human safety signals, setting up follow-up tests that mirror clinical dosing.

Overview

  • UC Irvine and University of Queensland researchers report in Cancer Research that inhibiting C5a–C5aR1 signaling prevented radiation-induced cognitive decline in mice.
  • Both C5ar1 gene knockout and the small-molecule inhibitor PMX205 preserved learning and memory in healthy and tumor-bearing mice after cranial irradiation.
  • Neuroinflammation and synaptic damage markers fell with C5aR1 blockade, indicating reduced microglial and astroglial activation and preserved neural connections.
  • Radiation’s anti-tumor efficacy was not diminished by C5aR1 inhibition, with tumor control outcomes matching or occasionally exceeding radiation alone.
  • The team plans studies using fractionated radiation, temozolomide combinations, and advanced mouse and patient-derived models to support translation toward clinical testing.