Antisecretory Factor Reduces Tumor Pressure and Exhibits Anti-Tumor Activity in Human Glioblastoma

Glioblastoma (GBM) is among the most aggressive cancers and progresses with developing high interstitial fluid pressure (IFP). Increased IFP is a barrier to drug uptake, but the relationship between mechanical/osmotic stresses and tumor biology remains unclear. Blocking shrinkage-sensitive sodium-potassium-chloride co-transporter 1 (NKKC1) with its inhibitor bumetanide hinders proliferation and invasion of GBM cells. However, its clinical application is limited by poor brain penetration and adverse-effects. We found that compression promotes GBM cell proliferation, an effect antagonized by either bumetanide or antisecretory factor (AF), an antisecretory protein with a proved safety in humans. AF and bumetanide inhibited osmotic adaptation of cultured GBM cells in a similar manner. Using a telemetry-based approach, AF administration reduced IFP in patient-derived GBM xenografts, decreased tumor growth, increased cellular uptake of chemotherapeutics, and promoted temozolomide-sensitivity in GBM xenografts. In conclusion, AF therapy represents a novel pressure-reducing strategy with anti-tumor activity to safely improve the outcome of GBM patients. 16 samples, no replicates, 4 treatment conditions, derived from 4 individual patients