Researchers at the University of Rochester Medical Center have developed a way to make a well-known breast cancer drug more effective against aggressive forms of the disease by altering the treatment's target mechanism.
Basal-like breast cancer is notoriously resistant to treatment due to a lack of three main receptors: the estrogen receptor, the progesterone receptor and the Her2/neu receptor, without which standard treatments like tamoxifen have trouble locating the cells to deliver their payload. Normally, according to the team's research published in EMBO Molecular Medicine, tamoxifen is used to block estrogen receptors on the outside of cancer cells. But the researchers studied a secondary drug effect pointing to two proteins, c-Cbl and Cdc42, on the cancer cells that keep them alive.
So by combining tamoxifen with an experimental drug called ML141 that inhibits those crucial proteins, the cancer cells became more vulnerable to the drug's toxic effects. Neither drug alone had the ability to induce basal-like cancer cell death in this way, but the combination of the two proved in animal and human cell culture studies to effectively neutralize them.
Also, because cancer cells have elevated levels of Cdc42 protein relative to normal cells, the ML141-tamoxifen combination selectively targets cancer stem cells while leaving healthy cells alone.
"Our work is very exciting because our approach simultaneously addresses two of the most critical challenges in cancer research--to increase the utility of existing therapies and to discover new vulnerabilities of cancer cells," said Mark Noble, one of the research team's leaders, in a statement. "Based on these discoveries, we are already pushing forward with new compounds and with new approaches that might make clinical translation of this discovery much more rapid than would occur with traditional drug-discovery approaches."
The National Institutes of Health, Susan G. Komen for the Cure, the U.S. Department of Defense and the New York State NYSTEM initiative all took an interest in the research, helping to fund it.