Temozolomide-Derived Therapeutic Strategies to Overcome Resistance in Glioblastoma

Glioblastoma multiforme (GBM) accounts for nearly half of malignant CNS tumors and has a dismal 5-year survival rate of 5.5%. The current standard of care comprises maximal surgical resection, followed by radiotherapy with concurrent temozolomide (TMZ) and subsequent adjuvant TMZ chemotherapy. While TMZ modestly extends survival, its efficacy is limited in patients with unmethylated MGMT promoters, representing over 50% of GBM cases. To improve TMZ's clinical performance, research has focused on structural modifications, TMZ-based hybrids and conjugates, nanoformulations, and rational combination therapies. This perspective summarizes medicinal chemistry approaches to optimize TMZ derivatives to overcome resistance in GBM. We also highlight clinical trial outcomes of TMZ-based combinatorial regimens. Continued advances in TMZ-derived drug development, together with emerging therapeutics such as immunotherapies and oncolytic virotherapies, hold considerable promise for improving treatment outcomes in GBM.