A new class of glioma drugs exploits tumors that lack the DNA repair enzyme MGMT; the drugs lead to the generation of cytotoxic DNA and selectively kill tumor cells without the risk of resistance, researchers report. The new approach may lead to new glioma treatments and may represent a new paradigm for designing therapeutics that exploit specific DNA repair defects to combat drug-resistant tumors. Fast-growing and highly aggressive, glioblastoma (GBM) is the most common form of malignant brain tumor. It is also one of the most lethal cancers, with only 1 in 20 patients surviving for 5 years after diagnosis. Although this cancer is treated with a combination of radiotherapy and the chemotherapy drug temozolomide (TMZ), drug resistance develops in many patients. As such, there is a dire need for new GBM treatments. Many GBM and glioma tumors lack the DNA repair protein MGMT – an attribute implicated in their ability to gain drug resistance. Here, Kingson Lin and colleagues present a new therapeutic approach, which leverages this lack of MGMT to kill GBM tumor cells selectively. Using a mechanism-based design approach, Lin et al. developed TMZ analogs that create a dynamic primary DNA lesion, which can be repaired in healthy cells with intact MGMT-mediated DNA repair mechanisms. However, cancer cells lacking MGMT expression cannot repair the damage. In these cells, the primary lesions slowly evolve, creating more and more toxic secondary DNA lesions that result in the selective killing of MGMT-deficient tumor cells. The authors found that the drug-induced selective tumor-cell killing had an acceptable toxicity profile in vitro and in vivo using a mouse model of TMZ-resistant human GBM. In a related Perspective, Roger Reddel and Adel Aref further discuss the study’s findings.
Mechanism-based design of agents that selectively target drug-resistant glioma
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