Decades Later, Tamoxifen Pushed in New Directions

Decades Later, Tamoxifen Pushed in New Directions

Tamoxifen, a time-honored breast cancer drug, has been back in the headlines lately because two separate clinical trials reported that 10 years of treatment is superior to the standard five years for many women with breast cancer.

The studies enrolled more than 15,000 women, and showed that 10 years of therapy reduced the risk of recurrence and death from early-stage, hormone-positive breast cancer. The news made a big splash at this year's American Society of Clinical Oncology (ASCO) meeting. Many oncologists believe the findings will change current practice worldwide; at a minimum it will create additional dialogue between patients and physicians about the risks versus benefits of extending tamoxifen therapy.

In the midst of the ASCO buzz, a Wilmot Cancer Center research team reported some very interesting findings of their own–on how to leverage the drug's various cellular activities so that it might work on more aggressive breast cancers.

Published in the journal EMBO Molecular Medicine, the research is a promising development for women with basal-like breast cancer, sometimes known as triple-negative disease. This subtype has a poor prognosis because it is notoriously resistant to treatment. Basal-like cancers lack the three most common breast cancer biomarkers (the estrogen receptor, the progesterone receptor and theHer2/neu receptor), and without these receptors, the usual front-line therapies are not effective.

Tamoxifen is known primarily for its ability to block estrogen receptors on the outside of cancer cells. However, newer studies have suggested that when tamoxifen is given in higher doses, it works through a second mechanism of action independent of the estrogen receptor. This second mechanism was the focus of the Wilmot laboratory.

Led by doctoral student Hsing-Yu Chen and Mark Noble, Ph.D., professor of Biomedical Genetics at URMC, the team studied the molecular mechanism that allows basal-like breast cancer cells to escape the secondary effects of tamoxifen, and discovered that two proteins are critical in this escape. One protein, called c-Cbl, controls the levels of multiple receptors that are critical for cancer cell function. A second protein, Cdc42, can inhibit c-Cbl and is responsible for the tumor's underlying resistance.

The team also discovered that by targeting Cdc42, and thus impending the inhibitor with an experimental drug compound known as ML141, they could restore c-Cbl's normal function. Through additional work in animal models and in human cell cultures, the team demonstrated that when ML141 is paired with tamoxifen, it enhances the ability of the drug to induce cancer cell death and suppress the growth of new cancer cells. Neither drug alone had the same effect on basal-like breast cells. Noble believes there is considerable value to targeting Cdc42, because elevated levels of the protein have been observed in multiple types of cancer.

The powerful ML141-tamoxifen drug combination looks like it has two more important features: It selectively targets cancer cells while sparing normal, healthy cells; and it appears to cripple cancer stem cells, the primitive cells responsible for initiating new tumors and for fueling the bulk of the tumor cell population.

"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 Noble, who also is a leader at UR's Stem Cell and Regenerative Medicine Institute. "Based on these discoveries, we are already pushing forward with new compounds and 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 funded the research. Co-authors include Yin Miranda Yang, Ph.D., and Brett Stevens, Ph.D.

Journal citation: Chen H-Y, Yang YM, Stevens BM, Noble M (2013) Inhibition of redox/Fyn/c-Cbl pathway function by Cdc42 controls tumour initiation capacity and tamoxifen sensitivity in basal-like breast cancer cells. EMBO Mol Med, DOI: 10.1002/emmm.201202140

Dialogue Summer 2013

Click here to download the print version of Dialogue