LAUSR

A vast literature demonstrates that aldehyde dehydrogenase-1A1 (ALDH1A1) mediates therapy resistance and is associated with poor prognosis across human cancers. In glioblastoma (GBM), ALDH1A1 expression above vs below the mean causes temozolomide and radiation resistance and is associated with a substantial reduction in survival (methylated MGMT 14.6 vs 32.9 months, P = .004; unmethylated MGMT: 12.6 vs 21.4 months P = .005), while knockdown of ALDH1A1 restores sensitivity to chemotherapy and radiation therapy. 1,2 ALDH1A1 is also a known mediator of resistance to EGFR (epidermal growth factor receptor) blockade and an activator of HIF1A. Aldehyde dehydrogenases detoxify anticancer drugs and function as anti-oxidants by reversing lipid peroxidation and repairing etheno-DNA adducts, thus maintaining REDOX homeostasis that confers chemotherapy and radiation failure. 3 ALDH1A1 also catalyzes the conversion of retinaldehyde to retinoic acid resulting in the stemness phenotype that causes tumor re-population. 4 These functions of ALDH1A1 make it a target of interest in two ongoing clinical trials of disulfiram in newly diagnosed and relapsed GBM. Against this background, recent observations that proton pump inhibitors (PPIs) are potent inducers of ALDH1A1 activity indicates a potential source of iatrogenesis. Omeprazole binds to the aldehyde binding site of ALDH1A1 thereby upregulating enzyme