Novel Strategies for Improved Treatment of O6-Methylguanine-DNA Methyltransferase Promoter-Methylated Glioma

Adult diffuse gliomas are primary brain tumors notorious for leading to devastating neurologic consequences from both tumor progression and therapeutic interventions. The arsenal of current established treatments primarily includes surgery, radiotherapy, and DNA alkylating chemotherapy agents. Unfortunately, even with aggressive treatments, long-term cure is typically not attainable, except in certain cases of low-grade gliomas amenable to complete surgical resection. Grade 4 glioblastoma (GBM) represents the most aggressive and most common type of glioma in adults, is often resistant to current therapies, and is associated with a median survival of approximately 15 months. While biomarker-based therapies for gliomas are limited, O6-methylguanine-DNA methyltransferase (MGMT) is one well-established prognostic marker in GBM and is associated with improved response to the alkylating agent temozolomide (TMZ). Methylation of the MGMT promoter leading to loss of MGMT expression occurs in approximately half of GBMs and 70-80% of anaplastic and low-grade gliomas. While MGMT promoter-methylated gliomas are responsive to TMZ, a characteristic resistance mechanism of mismatch repair loss often emerges, resulting in recurrent drug-resistant disease. In prior work, we identified a new TMZ derivative "KL-50" which overcomes resistance to TMZ driven by loss of mismatch repair in preclinical glioma models. KL-50 functions via a novel DNA-modifying mechanism involving evolution of a primary alkyl lesion to a DNA interstrand crosslink specifically in the absence of MGMT. Research is ongoing to establish this new class of agents as a potential improved therapy in human gliomas. In this review, we provide an overview of the history and evolution of alkylator use in GBM, discuss the mechanisms and pitfalls of current therapies including toxicity or susceptibility to resistance mechanisms, and present the potential of a new wave of DNA modifiers to improve outcomes in gliomas.