A combination of two targeted drugs--one that blocks protein breakdown and one that activates the programmed cell death pathway--reduces the number of tumor metastases in mouse models of kidney and breast cancer. The combination also prolonged overall survival in mice with kidney cancer.
Bortezomib blocks the activity of the proteasome, an enzyme complex which degrades misfolded or unwanted proteins. Bortezomib has been approved by the U.S. Food and Drug Administration for the treatment of multiple myeloma, but its activity against solid tumors is still being tested.
The immune system in both humans and mice may use the TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) pathway to eliminate precancerous cells by inducing programmed cell death, or apoptosis. Antibodies that bind to the TRAIL receptor can activate the cell death pathway, as does the TRAIL ligand. The research group led by Thomas Sayers, Ph.D., of SAIC-Fredrick Inc., at the National Cancer Institute in Frederick, Md., had previously shown that bortezomib sensitizes some tumors to TRAIL-mediated cell death.
In the current study, the researchers tested whether the combination of bortezomib and an antibody that binds and stimulates the TRAIL receptor-2, called MD5-1, was more effective at killing cancer cells grown in culture than either drug alone. They also tested the combination's ability to improve the outcome of mice that had been injected intravenously with kidney and breast cancer cell lines.
Treating cancer cells with the combination of bortezomib and MD5-1 increased cell death in kidney cancer cells from 34 percent to 95 percent, compared with MD5-1 alone, and from 20 percent to 85 percent in the breast cancer cells. Mice treated with the combination showed a highly significant reduction in metastases as compared with either drug alone. Overall survival was extended in kidney cancer-bearing mice treated with the combination, with 73 percent of the mice alive at 180 days, compared with a median survival of 42 days in the mice treated with the single-agent MD5-1.
"This regimen showed no evidence of host toxicity," the authors write. "These results thus provide a rationale for the administration of bortezomib in vivo to sensitize tumor cells to the apoptotic effects of TRAIL receptor agonist antibodies or TRAIL ligand to promote solid tumor regression."
This research was reported April 29 in the Journal of the National Cancer Institute.
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