Abstract
Glioblastoma, isocitrate dehydrogenase (IDH) wild type, is the most common primary intracranial malignant tumor, with a median survival of less than 2 years.1,2 While numerous studies have proposed novel treatment strategies, few have successfully translated into clinical practice. Recent efforts have focused on targeted therapies aimed at blocking glioblastoma recurrent drivers, immunotherapies with various strategies, or anti-angiogenic agents. The DNA alkylating agent temozolomide (TMZ), combined with radiotherapy and tumor-treating fields, is still the standard postsurgical treatment.3 However, most of the patients eventually acquire resistance to TMZ through mismatch repair (MMR) pathway deficiency.4 Only a few trials have tested strategies to optimize the use of currently available alkylating agents, increasing their activity by developing novel, more potent compounds, or combining them with DNA damage response inhibitors.5
Mechanistically, TMZ induces O6-methylguanine lesions, which lead to DNA double-strand breaks and subsequent tumor cell death mediated by the recruitment of MMR at the site of DNA damage in MGMT-deficient cells. Consequently, cells inactivating the MMR pathway through mutations or epigenetic mechanisms develop high resistance to TMZ.6 Lomustine (CCNU) is a nitrosourea that acts independently of MMR by introducing inter-strand DNA crosslinks and leads to carbamoylating amino acids.7 MMR-deficient cells can sometimes retain sensitivity to CCNU,6 but the toxicities (eg, hematological, lung) associated with CCNU limit its use in the clinic. A phase III trial combining CCNU with the standard treatment demonstrated improved overall survival in newly diagnosed MGMT-deficient glioblastoma.5 However, significant toxicities, with over half of the patients experiencing adverse events of grade 3 or higher, have limited its clinical utility.