Highlights
- Potent ALDH1A1-activating proton pump inhibitors (PA-PPIs) are linked to inferior progression-free and overall survival in newly diagnosed glioblastoma patients.
- This negative association persists after adjustment for key prognostic factors including MGMT methylation, steroid use, and extent of tumor resection.
- No adverse survival impact was observed with the use of other antacid drugs, delineating a potential drug class-specific effect.
- Mechanistically, PPI-induced ALDH1A1 activation may confer protection against oxidative stress and therapy resistance, warranting translational investigations.
Background
Glioblastoma (GBM) represents the most aggressive primary malignant brain tumor in adults, with median survival typically less than two years despite multimodal standard of care involving maximal safe resection, radiotherapy, and temozolomide chemotherapy. Corticosteroids are routinely administered to control peritumoral edema, but their long-term use predisposes to gastrointestinal complications including gastritis and peptic ulcers. Proton pump inhibitors (PPIs) are frequently prescribed as gastroprotective agents in this context.
However, emerging evidence implicates an unforeseen role of PPIs, particularly potent ALDH1A1-activating PPIs (PA-PPIs), in modulating tumor biology. ALDH1A1, an enzyme involved in aldehyde detoxification, has been linked to cancer stem-cell phenotypes, oxidative stress resistance, and chemoradiotherapy resistance in glioma models. Understanding the clinical impact of PPI use on glioblastoma survival outcomes is therefore of substantial relevance for therapeutic decision-making.
Key Content
Chronological Development of Evidence
Until recently, the relationship between PPI use and glioma outcomes had been unexplored comprehensively in clinical cohorts. Earlier preclinical studies identified ALDH1A1 as a mediator of resistance mechanisms in glioblastoma cells, suggesting a plausible biological interaction with agents influencing ALDH activity. This hypothesis prompted integrated analyses within clinical trial datasets to delineate the impact of PA-PPIs.
Meta-Analysis from Randomized Controlled Trials (2008-2020)
A landmark secondary meta-analysis leveraging prospectively collected individual patient data from five randomized clinical trials, encompassing 2,981 newly diagnosed glioblastoma patients, was published in 2025 (Le Rhun et al.). The trials spanned diverse geographic regions and encompassed standard-of-care regimens with temozolomide.
PA-PPI use was assessed at baseline and at landmarks corresponding to initiation of maintenance temozolomide cycles 1 and 4 and completion of cycle 6. The outcomes analyzed were progression-free survival (PFS) and overall survival (OS).
Univariate analyses revealed significantly worse PFS and OS among patients receiving PA-PPIs across all time points examined. Multivariate models, adjusting for age, sex, Karnofsky performance status, corticosteroid use, extent of resection, and methylation status of MGMT, corroborated these findings. Hazard ratios for PFS ranged from 1.14 to 1.31, and for OS from 1.14 to 1.34 at relevant landmarks, indicating a consistent detrimental effect.
Importantly, use of other antacid therapies (e.g., H2 receptor antagonists) showed no significant survival impact, reinforcing a potential mechanistic specificity of PA-PPIs related to ALDH1A1 activation rather than acid suppression alone. Subgroup analyses demonstrated that this negative association was independent of MGMT promoter methylation and steroid usage, two critical prognostic variables in glioblastoma.
Mechanistic Insights
ALDH1A1 functions to detoxify reactive aldehydes, protect cells from oxidative damage, and has been linked to cancer stem-like properties in glioma cells. PPIs such as omeprazole and esomeprazole have been shown experimentally to activate ALDH1A1 enzymatic activity, potentially facilitating glioma cell survival under therapeutic pressures such as radiation and alkylating chemotherapy.
These findings indicate that PA-PPI use might paradoxically induce resistance pathways, leading to earlier tumor progression and poorer overall survival. Nonetheless, clinical outcome associations do not yet confirm causality, and preclinical validation and biomarker translation are needed.
Expert Commentary
This robust meta-analysis underscores a clinically significant association between PA-PPI administration and poorer survival outcomes in glioblastoma, a finding with immediate practice implications. Given that effective alternatives exist for gastrointestinal prophylaxis in steroid-treated patients, clinicians should consider avoiding PA-PPIs in this vulnerable population.
While retrospective and prospective observational studies have limitations including confounding by indication, this pooled dataset from randomized trials with meticulous clinical annotation strengthens the evidence. The independent effect from known prognostic factors and the absence of association with other antacids suggest a genuine drug-class effect rather than a mere marker of illness severity.
The biological plausibility of PPI-induced ALDH1A1 activation mediating therapy resistance aligns with emerging paradigms of glioma stem cell biology. Nevertheless, prospective interventional studies to assess discontinuation or substitution of PA-PPIs during glioblastoma treatment and translational work to directly measure ALDH1A1 activity in patient tumors are critical next steps.
Conclusion
Cumulative evidence indicates that potent ALDH1A1-activating proton pump inhibitors negatively impact survival outcomes in patients with newly diagnosed glioblastoma. These findings should prompt oncologists to reevaluate PPI prescribing practices, favoring alternative gastric protective strategies.
Future research priorities include elucidating the mechanistic pathways by which PPIs influence glioma cell resistance, validating ALDH1A1 activity as a biomarker, and conducting prospective clinical trials to confirm these observational findings. Cautious and judicious use of PPIs represents a modifiable factor with potential to improve glioblastoma patient outcomes.
References
- Le Rhun E, Sain D, Erridge SC, et al. Proton Pump Inhibitor Use and Survival in Patients With Newly Diagnosed Glioblastoma. JAMA Netw Open. 2025;8(11):e2545578. doi:10.1001/jamanetworkopen.2025.45578. PMID: 41288972.
- Chen R, et al. ALDH1A1 and glioblastoma stem cells: mechanisms and therapeutic implications. Neuro Oncol. 2023;25(5):891-904. doi:10.1093/neuonc/noac234.
- Stupp R, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987-96. doi:10.1056/NEJMoa043330.
- Lind BL, et al. Impact of proton pump inhibitors on cancer stem cell pathways: preclinical and clinical perspectives. Cancer Lett. 2022;548:215-221. doi:10.1016/j.canlet.2022.01.017.
