Beating Glioblastoma (Multiforme) with Chameleon Compounds

Tomorrow, 8 June will be World Brain Tumor Day and it is an opportunity to raise awareness of these pathologies. As you know, one of the images we often use represents glioblastoma as a chameleon. The name that until recently was used for GBM was in fact glioblastoma multiforme to indicate the fact that from a genetic point of view glioblastoma is often different from one patient to another and sometimes even in the same patient and also that glioblastoma, being of stem cell origin, mutates and develops resistance to drugs. I am therefore very happy to present a new pre-clinical phase study that nevertheless has considerable potential, close to this anniversary.

The research, published in the Journal of the American Chemical Society, represents a crucial step in the development of “chameleon” compounds that could be used to target a range of cancers such as drug-resistant brain tumors without harming surrounding healthy tissue.

For decades, patients with glioblastoma have been treated with a drug called temozolomide. However, most patients develop resistance to temozolomide within a year. The five-year survival rate for glioblastoma patients is less than 5%. In 2022, chemist Seth Herzon and radiation oncologist Ranjit Bindra, both at Yale University, developed a new strategy to target glioblastomas more effectively. They created a class of anticancer molecules, “chameleon” compounds, that exploit a defect in a DNA repair protein known as O6-methylguanine DNA methyltransferase (MGMT).

Many cancer cells, including glioblastomas, lack the MGMT protein. The new chameleon compounds are designed to damage DNA in cancer cells that lack MGMT. The chameleon compounds begin to damage DNA by depositing primary lesions on the DNA that evolve over time into highly toxic secondary lesions known as interstrand crosslinks. MGMT protects the DNA of healthy tissue by repairing the primary lesions before they can develop into deadly interstrand crosslinks.

In their new study, authors Herzon and Bindra focused on their lead chameleon compound, KL-50. KL-50 is unique in that it forms DNA interstrand crosslinks only in a DNA repair-defective tumor. It spares healthy tissue. Several other anticancer compounds that initiate interstrand crosslinks have been developed, but they are not selective for cancer cells, which limits their usefulness.

The secret to KL-50’s success is its timing, the researchers say. KL-50 generates interstrand crosslinks more slowly than other cross-linking agents. This delay gives healthy cells enough time to utilize MGMT to prevent cross-linking. This unique profile suggests its potential for treating drug-resistant glioblastoma.