Dr Bindra on the Role of MGMT Loss on Resistance Mechanisms in Cancer

Ranjit S. Bindra, MD, PhD, Harvey and Kate Cushing professor, Therapeutic Radiology, professor of pathology, vice chair, Translational Research, Yale School of Medicine, scientific director, Chênevert Family Brain Tumor Center, Smilow Cancer Hospital, Yale Cancer Center, discusses a new class of DNA modifiers which selectively target tumor DNA with the goal of overcoming resistance mechanisms across multiple types of cancer.

In a study published in Science in 2021, Bindra and colleagues investigated the mechanism-based design of agents that selectively target drug-resistant cancer. O6-methylguanine methyl transferase (MGMT)–deficient tumors respond initially to temozolomide; however, they frequently acquire resistance through loss of the mismatch repair (MMR) pathway. Bindra and colleagues noted that the development of agents could be designed to overcome this resistance mechanism by selectively inducing MMR-independent cell killing in MGMT-silenced tumors.

Previous research also showed that a new class of molecules, called DNA modifiers, could exploit the loss of MGMT to produce cell killing of MGMT-deficient glioma cells. Investigators aimed to expand on the types of cancer were MGMT loss could be leveraged.

In a study presented at the 2023 AACR Annual Meeting, Bindra and colleagues conducted a deeper mechanistic dive into how these new molecules modify DNA and how they could overcome mechanisms of resistance across multiple tumor types, Bindra explains.

Additionally, in isogenic models and patient-derived xenograft models of glioma, the use of DNA modifiers was found to have a robust effect, even as a monotherapy, leading to significant improvements in overall survival in mouse models, Bindra notes.

Findings thus far support further research for these DNA modifiers in the clinic, Bindra continues. The multidisciplinary approach for developing these modifiers involved experts in synthetic chemistry, basic DNA repair, radial biology, translational oncology, drug development, and clinical research, Bindra concludes.