Effects of inhibition of carbonic anhydrases 9 and 12 by E7070 in vitro and in vivo: Implications on progression and therapeutics of glioblastomas

Abstract

Glioblastoma is the most common and aggressive of primary brain tumors. Despite technological advances in the surgical procedure, followed by radiotherapy and chemotherapy, the average survival of patients is 12 to 15 months. This type of tumor has high cellular heterogeneity, with complex genetic alterations that reflect high genomic instability and have persistent malignant progression, characterized by spread and invasion through the brain, resistance to traditional and new therapeutic targets and damage to normal brain tissue. An important factor for tumor progression is the acidification of the environment that is promoted by carbonic anhydrases (CAs) 9 and 12, directing to the acquisition of metastatic phenotype and chemoresistance to anticancer drugs. These processes can be reversed by specific inhibitors of CAs. E7070, a membrane waterproof sulfonamide, is a new drug for cancer treatment, with potent inhibition of these enzymes. It has in vitro and in vivo activity and prevents cell cycle progression in tumor cells. A better understanding of complex molecular and cell mechanisms, that lead to tumor progression, is an important prerequisite for the identification of new and more effective therapeutic strategies, aiming to improve survival of patients. Thus, in this project researchers propose studying the expression and the in vitro effects of inhibition of the 9/12 CAs by E7070 (alone or in combination with the currently used treatment) in chemoresistance, invasion, proliferation and apoptosis of cell lines and SSEA-1+ stem cells subjected to hypoxia. Among the studied genes, researchers will select one to analyze in in vivo model of immunocompomised mice, the effects of E7070 in the inhibition of tumor progression and, thus, survival.