Revisiting an old therapy for new, promising combinations: Biology and perspectives of lomustine in glioma treatment

The alkylating agents temozolomide (TMZ) and lomustine (CCNU) are the most effective systemic agents for malignant gliomas. However, resistance-whether intrinsic or acquired-inevitably develops in all patients, and these tumors remain incurable. Although CCNU has demonstrated clinical benefit, its clinical use has been relatively limited due to a less favorable safety profile compared to TMZ. Recently, interest in CCNU and other nitrosoureas has been renewed in light of positive clinical trials in both adult and pediatric gliomas. Despite this renewed attention, critical questions remain unaddressed regarding the use of nitrosoureas. While resistance and response to temozolomide have been associated with the status of both MGMT and the mismatch repair DNA repair pathway, our understanding of the unique mechanisms of resistance to nitrosoureas beyond MGMT remains limited. Recent advances in molecular biology, preclinical models, and the use of longitudinal analyses of treated samples provide new insights, offering opportunities to refine clinical use and develop novel strategies. In this review, we explore the current role of nitrosoureas in glioma treatment, examine known and emerging mechanisms of sensitivity and resistance to these agents, and explore the potential for combination approaches to enhance their efficacy.