2026-04-26T23:12:01Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/260142025-12-18T12:52:28Zcom_20.500.12105_19586com_20.500.12105_2202col_20.500.12105_19587

00925njm 22002777a 4500 dc Jiménez-Alcázar, Miguel author Curiel-García, Álvaro author Nogales, Paula author Perales-Patón, Javier author Schuhmacher, Alberto J author Galán-Ganga, Marcos author Zhu, Lucía author Lowe, Scott W author Al-Shahrour, Fatima author Squatrito, Massimo author 2021-06 Glioblastoma (GBM) is the most frequent and aggressive primary tumor type in the central nervous system in adults. Resistance to chemotherapy remains one of the major obstacles in GBM treatment. Identifying and overcoming the mechanisms of therapy resistance is instrumental to develop novel therapeutic approaches for patients with GBM. To determine the major drivers of temozolomide (TMZ) sensitivity, we performed shRNA screenings in GBM lines with different O6-methylguanine-DNA methyl-transferase (MGMT) status. We then evaluated dianhydrogalactitol (Val-083), a small alkylating molecule that induces interstrand DNA crosslinking, as a potential treatment to bypass TMZ-resistance mechanisms. We found that loss of mismatch repair (MMR) components and MGMT expression are mutually exclusive mechanisms driving TMZ resistance Treatment of established GBM cells and tumorsphere lines with Val-083 induces DNA damage and cell-cycle arrest in G-M phase, independently of MGMT or MMR status, thus circumventing conventional resistance mechanisms to TMZ. Combination of TMZ and Val-083 shows a synergic cytotoxic effect in tumor cells , and We propose this combinatorial treatment as a potential approach for patients with GBM. Mol Cancer Ther. 2021 Jun;20(6):1029-1038. https://hdl.handle.net/20.500.12105/26014 33846235 Molecular Cancer Therapeutics Dianhydrogalactitol Overcomes Multiple Temozolomide Resistance Mechanisms in Glioblastoma.