On December 14, 2020 Amgen reported that osteoporosis drug denosumab is approved as Xgeva for the prevention and treatment of some bone metastases in cancer (Press release, Amgen, DEC 14, 2020, View Source [SID1234572972]). But could the drug’s mechanism of action help breast cancer patients respond to immunotherapy drugs that typically don’t work well in those tumors?
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That was the premise behind a new study led by the Bellvitge Institute for Biomedical Research (IDIBELL) in Spain and partially funded by Amgen. The researchers studied cells from mouse models and from premenopausal patients with luminal breast cancer to determine whether Xgeva’s inhibition of a signaling pathway called RANK might make the tumor cells more sensitive to immunotherapy.
They discovered that the RANK protein is involved in the communication between cancer cells and immune cells. Inhibiting RANK in the breast tumor cells improved responses to drugs that block the immune checkpoints CTLA-4 and PD-L1, they reported in the journal Nature Communications.
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The researchers started by showing in mice that inhibiting the RANK protein boosts the recruitment of immune cells to breast tumors. Inhibiting RANK and PD-L1 together cancer reduced tumor growth in half the tumors studied, while blocking PD-L1 alone had no effect. Their research suggested that cancer cells use RANK as "a possible escape route" from immunotherapy, according to a statement.
They went on to study cells from patients that participated in a clinical trial of Xgeva in premenopausal women with early-stage breast cancer. During the trial, patients received two doses of Xgeva before surgery. The study, which enrolled 27 participants, was ended in 2018 because of a recruitment shortfall, but the Spanish researchers were able to analyze tumor samples from 24 of the patients to back up their mouse findings.
They found that while the short course of Xgeva did inhibit the RANK protein, it did not shrink tumors or enhance survival. But, in most of the tumor samples, they found a significant increase in immune cells.
Some immune checkpoint inhibitors, such as Merck’s PD-1 blocker Keytruda, are approved for use in breast cancer, but improving their efficacy in tough-to-treat tumors is a major focus of research. Several academic teams are investigating the roles of different tumor-promoting proteins in suppressing responses to immunotherapy. Earlier this year, for example, a University of Cincinnati team showed it could improve PD-1 and CTLA-4 inhibition by blocking a protein called FIP200.
The IDIBELL-led team noted that during the clinical trial of pre-surgery administration of Xgeva, researchers identified biomarkers that might help clinicians select patients most likely to respond to a combination of RANK inhibition and immunotherapy.
"This strategy could turn immunologically cold breast cancers into [tumors] sensitive to the immune system activity," said co-author Eva Gonzalez-Suarez of the Spanish National Cancer Research Center in the statement.