Exploit DNA repair defects to selectively kill drug-resistant tumors

Fast-growing and highly aggressive, glioblastoma is the most common form of malignant brain tumor. It is also one of the deadliest cancers: only 1 in 20 patients survive for 5 years after diagnosis.

Although this cancer is treated with a combination of radiation therapy and the chemotherapy drug temozolomide, many patients develop resistance to the drugs. Given this situation, there is a great need for new treatments against glioblastoma.

Many glioblastoma and glioma tumors lack MGMT, a DNA repair protein, an attribute implicated in their ability to gain drug resistance.

Now, the team led by Kingson Lin, from Yale University in the United States, presents a new therapeutic approach that takes advantage of this lack of MGMT to selectively kill glioblastoma tumor cells.

Lin and colleagues developed temozolomide analogs that create a dynamic primary DNA lesion that is repairable in healthy cells with intact MGMT-mediated DNA repair mechanisms.

Artist’s rendering of DNA strands and brain cells. (Illustration: Amazings/NCYT)

However, cancer cells that lack MGMT expression cannot repair the damage. In these cells, the primary lesions evolve slowly, creating more and more secondary toxic DNA lesions that result in the selective destruction of MGMT-deficient tumor cells.

The study authors found that drug-induced selective tumor cell killing had an acceptable toxicity profile in vitro and in vivo using a mouse model of temozolomide-resistant human glioblastoma.

The study is titled “Mechanism-based design of agents that selectively target drug-resistant glioma.” And it has been published in the academic journal Science. (Source: AAAS)