New Brain Cancer Drug Uses Tumor Defect to Overcome Resistance

A new class of drugs that exploits a DNA repair defect common to many brain tumors to selectively kill cancer cells is reported in Science this week. Around half of glioblastoma tumors and more than two-thirds of gliomas lack the DNA repair protein MGMT. While these tumors respond initially to the widely used chemotherapeutic temozolomide, they frequently develop resistance through the loss of the mismatch repair (MMR) pathway. Aiming to overcome this resistance mechanism, a team of Yale University scientists developed temozolomide analogs that deposit a dynamic DNA lesion that can be repaired in normal cells with MGMT-mediated DNA repair mechanisms but not by cancer cells lacking MGMT. The result is MMR-independent cancer cell death with low toxicity in vitro and in vivo. The work, the researchers write, "may lead to new treatments for gliomas and may represent a new paradigm for designing chemotherapeutics that exploit specific DNA repair defects."