BMX-001, a selective radioprotector in phase II clinical trials, can reverse radiation-induced fibrosis when given three weeks after radiation

Radiation provides excellent tumor control in prostate cancer yet unavoidably harms adjacent healthy tissue via the generation of reactive oxygen species (ROS). Radiation-induced ROS is known to impact fibroblasts long after radiation, resulting in radiation-induced fibrosis (RIF), which can cause incontinence and other side effects that reduce patient quality of life. BMX-001, a manganese porphyrin designed to mimic superoxide dismutase, is in clinical trials as a selective radioprotector when given before and during radiation therapy. However, there have been no studies evaluating BMX-001 when given after radiation for its impacts on RIF. Mice were given pelvic radiation (7.5 Gy for 5 consecutive days) followed by BMX-001 three weeks after radiation. Fibroblasts and tissues were isolated two months following radiation. We found that BMX-001 returned radiation-induced alterations in fibroblast morphology to normal and reversed markers of fibroblast activation and senescence. BMX-001 also decreased collagen deposition six months after radiation. We found that overall, radiation resulted in reduced methylation two months after radiation, and BMX-001 administered three weeks after radiation modulated radiation-altered methylation patterns back to normal and restored normal expression of a fibrosis-associated gene CAMK2beta. BMX-001 also decreased radiation-induced DNA adduct 8-hydroxy-2'-deoxyguanosine (8-OHdG), which is known to interfere with methylation. BMX-001 was able to prevent DNA oxidation and restore normal methylation patterns in an oligonucleotide model of DNA oxidation and methylation. This study reveals the feasibility of agents to reverse fibrosis in pelvic radiation and suggests that BMX-001 may be effective when given after radiation. Overall design: Four total RNA-Seq samples of different treatments in mice: PBA, BuOE, PBS+raditation, and BuOE+radiation.