Researchers at The Wistar Institute in Philadelphia have identified an experimental drug that shows great promise in halting ovarian cancer progression. The treatment, which is currently in clinical trials for a number of cancers, is able to boost anti-tumor immunity and cause T-cells to directly target ovarian cancer cells.
The study, “BET Bromodomain Inhibition Promotes Anti-tumor Immunity by Suppressing PD-L1 Expression,” is published in the journal Cell Reports.
Ovarian cancer ranks fifth in cancer deaths among women, accounting for more deaths than any other cancer of the female reproductive system. Few effective treatments have been approved to treat this deadly cancer. Tumors evade anti-tumor immunity through inhibitory pathways that regulate the function of T lymphocytes, known as immune checkpoints.
The programmed cell death (PD)-1 protein is predominantly expressed on the surface of T-cells, while its ligands, such as PD-L1, are expressed on the surface of both immune and ovarian cancer cells.
The interaction between PD-1 and PD-L1 inhibits T-cell activity, reducing their ability to target and destroy the cancer cells. And the more PD-L1 a cancer expresses, the better the cancer evades immune surveillance. Inhibiting this interaction with antibodies that target the PD-1 pathway has shown great promise in a variety of cancers. However, patients taking these drugs often experience immune-related side effects.
“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, PhD, professor and co-program leader in the Gene Expression and Regulation program at The Wistar Institute and the study’s lead author, said in a news release.
In the new study, the team of researchers used ovarian cancer cell lines and evaluated a panel of 24 small molecule inhibitors to identify candidates with the ability to suppress PD-L1 expression. These small molecule inhibitors are preferable to antibodies that bind directly to PD-L1 because they target proteins or mutations that are specific to cancer cells while sparing healthy cells.
They discovered that bromodomain and extraterminal domain (BET) inhibitors were effective at suppressing PD-L1 activity. BET inhibitors are a class of drugs with anti-cancer and immunosuppressive properties that are currently being evaluated in clinical trials across the U.S. and Europe. In the new study, the researchers used JQ1, an experimental BET inhibitor.
BET inhibitors do not directly target PD-L1, but in the study the team showed that BRD4, a member of the BET family that is inhibited by JQ1, is a critical regulator of the expression of the PD-L1 protein. Therefore, by targeting BRD4, BET inhibitors can lower the levels of the PD-L1 and improve immune surveillance.
Importantly, since the BRD4 gene is frequently amplified in ovarian cancer, the researchers believe it may be used as a biomarker to establish which patients with ovarian cancer could benefit the most from treatments with BET inhibitors.
“Targeting PD-L1 appears to be an effective strategy for combating a variety of human cancers,” said Hengrui Zhu, PhD, a postdoctoral fellow in the Zhang lab and first author of the study. “With BET inhibitors, we believe we have found a powerful new addition to available therapeutic strategies for ovarian cancer.”
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