Research reveals glioma drug exploits DNA repair defects to selectively target drug-resistant tumors



NNA |
Updated:
July 28, 2022 11:48 p.m. STI

Washington [US], Jul 28 (ANI): New Class of Glioma Drugs Take Advantage of Tumors Lacking DNA Repair Enzyme MGMT; the drugs cause the generation of cytotoxic DNA and specifically kill tumor cells without the risk of developing resistance, according to the research.
The research results were published in the journal “Science”.
The new approach may lead to novel glioma treatments and may represent a new paradigm for designing therapies 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 deadliest cancers, with only 1 in 20 patients surviving for 5 years after diagnosis.

Although this cancer is treated with a combination of radiotherapy and temozolomide (TMZ), drug resistance develops in many patients. As such, there is an urgent need for new GBM treatments.
Many GBM tumors and gliomas lack the DNA repair protein MGMT – an attribute implicated in their ability to acquire drug resistance. Here, Kingson Lin and colleagues present a novel therapeutic approach, which takes advantage of this lack of MGMT to selectively kill GBM tumor cells.
Using a mechanism-based design approach, Lin et al. have developed analogs of TMZ that create dynamic primary DNA damage, 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 progress slowly, creating more and more toxic secondary DNA lesions that lead to the selective destruction of MGMT-deficient tumor cells.
The authors found that 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 discuss the study results in more detail (ANI)

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