Merck & Co is buying Yale spinout Modifi Biosciences, a deal that includes a preclinical asset designed to take on glioblastoma (GBM).
This could “change the whole landscape,” said Ranjit Bindra, M.D., Ph.D., Modifi co-founder and physician-scientist at the Yale School of Medicine.
GBM is the most common type of brain cancer and is a devastating disease, with a five-year survival rate of around 5%.
Modifi’s main asset, MOD-246, is a small molecule. Bindra noticed that some patients had cancers that were resistant to the chemotherapy drug temozolomide (TMZ). TMZ is used when the cancer cells have a nonfunctional version of the DNA repair protein called O6-methylguanine methyltransferase (MGMT), which occurs in about half of GBM cases. However, even when his patients had nonfunctional MGMT, TMZ sometimes didn’t work.
Bindra and colleagues discovered that TMZ kills cancer cells by adding methyl groups to the cells’ DNA. Normally, MGMT would remove these methyl groups, but, without it, the barrage of DNA modification activates a separate DNA repair pathway called mismatch repair (MMR). MMR detects all of the methyl groups and thinks the genome is damaged, so it shuts down replication and kills the cell.
TMZ exploits a cancer’s deficiency in one DNA repair pathway by using another, but it is ineffective if the cancer lacks a functional MMR pathway. To overcome this, researchers, including Seth Herzon, Ph.D., and Kingson Lin, M.D., Ph.D., developed a TMZ-based drug targeting MGMT directly, bypassing the need for MMR. This drug adds fluoroethyl groups to cancer DNA, causing cross-linking that blocks replication. They launched Modifi in 2021.
Merck and Modifi are now conducting IND-enabling studies for MOD-246, aiming to start clinic trials next year (2025).
