Two-hit strategy

Highly aggressive childhood brain cancers known as diffuse midline gliomas (DMGs)—including intrinsic pontine glioma (DIPG) and spinal cord glioma, among others—are diagnosed every year in a few hundred children, typically between the ages of 4 to 12. In a November paper in Science Translational Medicine, Ludwig Stanford researcher Michelle Monje and colleagues reported preclinical results showing that a new drug combination—panobinostat (a histone deacetylase inhibitor) and marizomib (a proteasome inhibitor)—could offer some hope for treating these incurable cancers. Previous work suggested that the drug panobinostat kills DMG cells, but the tumors tend to become resistant to the treatment. The team tested 2,706 single compounds and 9,195 drug combinations in cell cultures from patients’ tumors and found that the two-drug combination increased survival in mice implanted with tumors derived from those patient samples. It also interfered with the cancer cells’ ability to make a compound known as NAD, which plays a central role in cellular metabolism and energetics. Though NAD is essential to the survival of any cell, the two drugs synergize in a way that selectively affects NAD availability only in cancer cells. The researchers are now designing a clinical trial for the drug combination and for marizomib alone.

This article appeared in the April 2020 issue of Ludwig Link. Click here to download a PDF (1 MB).


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