Blocking the antioxidant enzyme PRX3 controlled disease in 67% of an early mesothelioma trial

Disease control rate is the most forgiving of the response endpoints. It pools patients whose tumors shrank with patients whose tumors merely failed to grow between two scans, and the University of Vermont release describing the trial does not say how many patients were enrolled ^[16]. Sixty-seven percent is two-thirds once rounded ^[18]. With twelve evaluable patients, reclassifying one is worth 8.3 percentage points ^[19].

Take the same care with the survival result. The report says the critically ill patients in the trial lived longer than patients receiving standard treatments ^[3]. That comparison sets this trial's participants against patients treated elsewhere. Phase one eligibility selects for people well enough to take an experimental dose, and a trial without its own control arm cannot separate that selection from the drug ^[1].

Deletion makes for a cleaner experiment: it removes the enzyme entirely, and the readout was whether the cells could still form tumors in an animal ^[8]. That supports PRX3 as a real dependency of this cancer. It says less about whether thiostrepton, the antibiotic the drug uses to disable the enzyme ^[4], hits PRX3 and little else in a patient. The selectivity argument rests on turnover: PRX3 is replaced faster in tumor cells than in healthy tissue, which the authors say may spare normal cells ^[9].

The failures of the earlier antioxidant trials do not argue for the reverse strategy on their own ^[7]. Tumor cells already produce more reactive oxygen species than normal cells and already lean on antioxidant enzymes to survive it ^[6], so removing one of those enzymes should hurt them first ^[9].

The population is small and poorly served. About 30,000 people are diagnosed worldwide each year, median survival is roughly 12 months, and about one in ten is alive at five years ^[12][13]. On those figures, some 27,000 of each year's patients will not reach five years ^[17]. Immunotherapy and chemotherapy help some of them ^[21]. "It's a disease of a significant unmet medical need," said Brian Cunniff, the University of Vermont professor who co-authored the Nature Communications paper with UVM research scientist Victoria Gibson ^[11][10].

Whether this extends to other cancers rests on the preclinical work. PRX3 is one of the antioxidant enzymes tumor cells raise to survive their own oxidative stress ^[6], so the same dependency could exist wherever that stress runs high. The deletion experiments were done in mesothelioma lines ^[8]. A 67% disease control rate in relapsed patients justifies a randomized trial in mesothelioma ^[1]. For other tumor types, the equivalent cell-line experiments come first.