PARP inhibitor drugs can be ‘tuned’ for better killing of tumor cells

Using innovative techniques, a new Penn Medicine study helps clear up mystery about why PARP-inhibiting compounds vary so much in their clinical effectiveness

A prospective “PARP inhibitor” drug that has struggled to show effectiveness in clinical trials against cancers can be structurally modified to greatly increase its power to kill tumor cells, researchers from Penn Medicine report in Science

Microscopic rendering of DNA helix repairing itself

The team also showed that PARP inhibitor compounds can be “tuned” in the opposite way so that they inhibit PARP-1 enzymes without killing cells, thus potentially making this class of drugs more useful for treating heart disease and other non-cancer conditions where inhibiting PARP-1 is the goal.

“We can now use this new understanding of how PARP inhibitors work to design compounds that are better tailored for specific conditions such as cancers vs. heart disease,” says senior author Ben Black, the Eldridge Reeves Johnson Foundation Professor of Biochemistry and Biophysics and co-director of the Penn Center for Genome Integrity at the Perelman School of Medicine.

PARP-1 is a DNA-repair enzyme that becomes particularly important for cell survival when other major DNA-repair factors such as BRCA proteins are missing. PARP inhibitors, of which four have been approved so far by the U.S. Food and Drug Administration, are thus considered especially promising as treatments for cancers driven by BRCA gene mutations. Tumor cells driven by BRCA mutations typically lack any BRCA-based DNA-repair capability, and their exposure to a PARP inhibitor further degrades their ability to fix DNA breaks, making the cells much more likely to die. PARP inhibitors have been shown to improve cancer patient outcomes when used alone or in combination with therapies such as chemo and radiation that induce DNA damage.

Read more at Penn Medicine News.