A Novel Glioblastoma Treatment Targets a Common DNA Modifying Mechanism

A Novel Glioblastoma Treatment Targets a Common DNA Modifying Mechanism ...

Glioblastoma (GBM) is the most common form of gliomaa tumor of the brain and spinal cord, making the need for new treatment strategies urgent. The current treatment approach involves a well-known GBM mechanism: decreased expression of the DNA repair enzyme O6-methylguanine methyltransferase (MGMT).

This paper is published in Science, entitled Mechanism-based design of agents that selectively target drug-resistant glioma.

Ranjit Bindra, MD, PhD, professor of therapeutic radiology at Yale School of Medicine, and Modifi Bio co-founder, believes this approach redefines the rules on how to selectively kill cancer cells via direct DNA modification, and positions our company as a leader in this exciting field of oncology drug development.

The agents work by generating a primary DNA lesion that can be repaired by healthy cells, because of their intact DNA repair mechanisms. Cancer cells that lack DNA repair machinery are unable to repair the damage; the result is more harmful secondary lesions (toxic DNA interstrand cross-link (ICL)), which lead to selective tumor cell death.

This method, according to the authors, creates a dynamic DNA lesion that can be reversed by MGMT, but evolves slowly into an interstrand cross-link in MGMT-deficient settings, resulting in MMR-dependent cell death with low toxicity in vitro and in vivo.

Because ICLs formation is slow, most of the primary lesions will be able to be repaired in normal cells. So, the drugs should have low toxicities. And, because ICLs mechanism cannot be evaded by mismatch repair mutations, there should be less resistance.

A new class of molecules has been discovered to be effective and selective against cancer cells that lack MGMT. Approximately half of all glioblastomas and up to 80% of gliomas lack MGMT, suggesting that this technique may work across many tumor types.

Modifi Bio, which recently raised $6.4 million in seed money, intends to file an investigational new drug application with the FDA in anticipation of Phase I clinical trials in 2024.

Roger Stupp, MD, professor of neurological surgery and chief of neuro-oncology at Northwestern University, believes that novel therapies for this form of brain cancer are required for the first time in over two decades. Stupp first published the groundbreaking research in 1986, which sets the standard of care for glioma.

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