Wistar Institute scientists have found a class of drugs that effectively dampened PD-L1 activity in ovarian cancer, even though it does not directly target PD-L1. Called bromodomain and extraterminal domain (BET) inhibitors, multiple candidates are in clinical trials for other cancers.
The interaction between the PD-1 protein and its ligand, PD-L1, blocks T cells from fighting tumor growth. But antibody-based drugs that disrupt this interaction can cause immune-related side effects, the scientists said in a statement.
“We wanted to explore anti-PD-L1 therapies specifically for ovarian cancer, but we also wanted to determine if other drugs that did not cause these negative anti-PD-L1 antibody-related side effects could be used to target this cancer-promoting pathway,” said Rugang Zhang, lead author of the study and a professor at the Wistar Institute.
They came upon BET inhibitors in their search for small molecule inhibitors, which inhibit cancer progression by targeting cells with cancer-associated mutations or proteins without harming healthy cells. They tested the BET inhibitor JQ1 in epithelial ovarian cancer cell lines and found it effectively suppressed PD-L1 activity and tamped down inflammatory responses, according to the statement.
While BET inhibitors do not specifically target PD-1/PD-L1, they work because the BET protein BRD4 regulates the expression of PD-L1, the researchers said. In ovarian cancer, cells tend to express higher levels of the BRD4 gene, so it could also be used as a biomarker to select patients who could benefit from treatment with BET inhibitors.
Merck markets the PD-1 drug Keytruda, while Bristol-Myers Squibb markets Opdivo. In July, Pfizer and Merck KGaA kicked off a Phase III trial combining a PD-L1 drug and platinum-based chemotherapy in epithelial ovarian cancer. Meanwhile, BET inhibitors are in clinical trials for various cancers, including hematologic malignancies and NUT midline carcinoma.
To view this entire article on FierceBiotech.com, please click here.