How PARP inhibitors might prove useful in more than just BRCA cancers

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Combining PARP inhibitors with BET inhibitors may expand their efficacy in different tumor types.

PARP inhibitor Lynparza (olaparib) has been embraced by oncologists treating women with BRCA-mutant ovarian cancer, and the AstraZeneca drug is also showing promise in breast cancers that harbor the same mutations. But scientists led by the University of Pennsylvania believe Lynparza may be able to kill cancer cells that don’t have the mutations—provided it’s paired with a helper compound.

The research team showed that a rising class of compounds known as BET inhibitors, when paired with Lynparza, slow tumor growth in mouse models of breast and ovarian cancer. They believe the combo, which was also well tolerated by the animals, could prove useful both for overcoming resistance to PARP inhibitors and for treating cancers that don’t harbor BRCA mutations. They published their findings in the journal Science Translational Medicine.

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Using a drug screen, the team searched for compounds that would allow Lynparza to kill cancer cells that lack BRCA mutations. They landed on JQ1, a compound that inhibits BET, a family of proteins known to drive some cancer-causing genes. BET inhibitors similar to JQ1 are currently in clinical trials. They include GlaxoSmithKline’s GSK525762, which is currently being tested in breast, colon and other cancers.

The scientists believe BET inhibitors work by preventing cancer cells from repairing their DNA, as do PARP inhibitors. But as many as 50% of ovarian cancer patients with BRCA mutations don’t benefit from PARP inhibitors because the cancer cells learn to escape the drugs’ effects, sometimes by developing secondary mutations, the researchers wrote. BET inhibitors seem to resensitize cancer cells, enhancing the DNA damage that leads to their demise.

And the combo may ultimately treat other cancers, as well. The researchers saw evidence of response to BET inhibition in 20 common cancer types, they reported.

RELATED: AZ looks to extend PARP lead with solid Lynparza breast cancer data

Several research groups are searching for new ways to improve the treatment outlook for ovarian cancer patients. Last year, Wistar Institute scientists published data suggesting the BET inhibitors dampen the activity of PD-L1, a “checkpoint” that prevents the immune system from attacking cancer. And earlier this year, another Penn team described a new imaging test that can measure the amount of PARP-1 enzyme in ovarian tumors, which could help identify patients most likely to respond.

Lynparza was the first FDA-approved PARP inhibitor, but the field has definitely taken off since the drug launched three years ago. Rubraca, a PARP inhibitor from Clovis Oncology, was approved for cases of ovarian cancer last December, and Tesaro’s Zejula got the thumbs-up in March. AstraZeneca is gearing up for an FDA submission in breast cancer this year.