Turning on the body’s inflammasome with epigenetic therapy may improve the efficacy of PARP inhibitors across multiple tumor types, possibly expanding the therapy’s application to new cancers, researchers reported in Proceedings of the National Academy of Sciences.
The inflammasome is a protein signaling network that can cause a DNA repair defect-like state in cancer cells, triggering an immune response to cancer when paired with PARP inhibitors. In laboratory models, the researchers used the epigenetic drug 5-azacytidine to make ovarian and triple-negative breast cancer cells appear and behave as if they had BRCA variants, sensitizing cancers to respond to PARP inhibitors when they wouldn’t normally do so.
BRCA variants occur naturally in only a small number of breast and ovarian cancers, the researchers reported, and so far those cancers have been the only clinical indication for PARP inhibitors. Turning on their features in other cancers may open the door for new treatment options in more patients.
“We believe we have uncovered a novel relationship in which the drug not only primes the immune response but also causes the breast and ovarian cancer cells to act as if they have a BRCA mutation. We think this reveals a new mechanism that has not previously been linked to immune therapy response,” the researchers said.
They are planning phase I and II studies to further test their findings.