Vacuolar ATPase and Drug Resistance of High Grade Gliomas: a Study to Investigate Possible Therapeutic Roles for Proton Pump Inhibitors

GBMs are still considered tumors with few available treatment options that are able only to achieve a temporary local control of the disease. In case of a GBM, tumor recurrence is generally expected within 12 months and it is due to the presence of marginal tumoral cells with pro-oncogenic molecular phenotypes that are resistant to actual chemotherapies and to radiation therapy. In particular, in case of GBM it is possible to distinguish three neoplastic layers within the tumor that show different molecular patterns: the central core; the intermediate layer and the peripheral layer. Nowadays, surgery still represent the first treatment option in case of suspected GBM and it aims to remove the contrast enhancing lesion seen at the pre-operative brain MRI. In particular, the peripheral layer is made of low replicating cells and it can be considered normal when tissue sampling is made far from the tumor cavity. In fact, Clavreul et al. in 2015 demonstrated that peripheral GBM layer contains glioblastoma-associated stromal cell (GASC) that can show different carcinogenic properties and that are probably responsible for tumor recurrence. These findings can be considered in line with previous studies that showed some invasive tumor cells, various types of reactive cells, and angiogenesis with different immunophenotypes in peritumoral brain edema.

Nevertheless, some research teams are trying to understand if surgical removal of peritumoral FLAIR hyperintensity is able to reduce the tumor recurrence rate prolonging the OS.

Metabolism of GBMs is mainly anaerobial and it is sustained by glycolysis. Anaerobial glycolysis is a simple metabolic reaction that leads to the transformation of glucose in ATP and lactates. Glucose is delivered to the tumor through neoangiogenetic processes. Production of a significant amount of lactates determines a decrease of intracellular pH that is counterbalanced by V-ATPase activity through the extrusion of H+ ions from the intracellular to the extracellular environment. In vitro inhibition of V-ATPAse has proved to increase CSC apoptosis due to decrease of intracellular pH.

Moreover, increased V-ATPase activity determines an extrusion of H+ ions in the extracellular environment that can positively affect different pro-tumoral activities. In fact, a decrease of extracellular pH leads to activation of proteases able to destroy the extracellular matrix. Such activity enhances tumor spreading. Moreover, a low extracellular pH can reduce the efficacy of antineoplastic agents since a low pH might affect the structural integrity of drugs and their ability to pass through the plasmatic membrane. Finally, V-ATPase can act as an active pump able to excrete antineoplastic agents.

For this reason, PPIs are considered new anti-cancer drugs able to increase tumoral cell death, reduce tumor invasion and increase chemotherapy efficacy.