Discovery Could Lead to New Breast Cancer Drugs

Eric Prossnitz, PhD, hopes to help many of the 12% of American women who are projected to be diagnosed with breast cancer in their lifetimes. He and his team have recently completed studies on a compound that they think could be made to attack breast cancer cells differently than current drugs. Their work is reported in the November online issue of Cell Chemical Biology.

Prossnitz understands firsthand the long path between discovery and U.S. Food and Drug Administration approval. A professor and cancer scientist at The University of New Mexico Comprehensive Cancer Center, he has studied breast cancer for the past 15 years. One of the compounds that he and his team discovered in 2006 has been licensed to Linnaeus Therapeutics for the treatment of melanoma and other cancers. Phase I clinical trials began at the UNM Comprehensive Cancer Center in 2019.

Prossnitz remains cautiously optimistic that the compound he and his team are now studying could help thousands of women. According to the National Cancer Institute’s Surveillance, Epidemiology and End Results program, more than 80% of women with breast cancer have estrogen receptor-positive (ER+) breast cancer.

The anti-hormonal breast cancer drugs available — drugs like tamoxifen and fulvestrant — work very well, but they work in only about two-thirds of the women with ER+ breast cancers. And, some of these women initially respond but then their breast cancer comes back in a form that resists the drug.

“It’s a huge number of women,” Prossnitz says. In 2019 alone, more than 60,000 women could face a new or recurrent ER+ breast cancer that won’t respond to anti-hormonal therapy.

Prossnitz and his team discovered some years ago that another cell receptor responds to anti-hormonal drugs. They named it GPER, for G protein-coupled estrogen receptor. While the primary estrogen receptor, ER-alpha, resides primarily inside the nucleus of a cell, GPER sits within cell membranes.

Tamoxifen, and drugs like it, block the ER-alpha receptor, while fulvestrant and similar drugs induce the cell to degrade it. By blocking or degrading the ER-alpha receptor, these anti-hormonal drugs greatly reduce the signal for the cancer cell to grow and reproduce. But, as Prossnitz and his team have previously shown, they also activate GPER, and GPER signals the cell to keep growing and reproducing.

“ER-alpha is the one [receptor] that plays an important role in ER+ breast cancer,” Prossnitz says.

Most breast cancer cells follow the ER-alpha signal and die on schedule when ER-alpha is blocked or degraded. But a very small number of breast cancer cells may follow the GPER signal and survive. And those cells can grow into aggressive tumors that no longer respond to anti-hormonal drugs.

Prossnitz and his team discovered a compound some years ago called AB-1 that binds to ER-alpha but does not activate GPER, thereby avoiding the undesirable side effect of current anti-hormonal drugs. In their Cell Chemical Biology paper, they report their studies that describe AB-1’s unique binding and activity behavior.

As they’ve done previously, Prossnitz and his team are working to change the structure of AB-1 to control its properties more tightly, before they progress to preclinical studies. Prossnitz is familiar with the path, and again, he hopes to develop a drug that will benefit many women with breast cancer.

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“A Selective Ligand for Estrogen Receptor Proteins Discriminates Rapid and Genomic Signaling” was published online on November 6, 2019, and will be published in the December 19 print edition of Cell Chemical Biology. Authors are: Chetana M. Revankar, Cristian G. Bologa, Richard A. Pepermans, Geetanjali Sharma, Whitney K. Petrie, Sara N. Alcon, Angela S. Field, Chinnasamy Ramesh, Matthew A. Parker, Nikolay P. Savchuk, Larry A. Sklar, Helen J. Hathaway, Jeffrey B. Arterburn, Tudor I. Oprea, and Eric R. Prossnitz.

Eric Prossnitz, PhD, is a Distinguished Professor and Chief of the Division of Molecular Medicine, in the Department of Internal Medicine, at The University of New Mexico School of Medicine. He co-leads the Cancer Therapeutics research program at the UNM Comprehensive Cancer Center.

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