Early-Stage Research on Dual-Action Estrogen Receptor Inhibitors for Breast Cancer

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A set of compounds developed by scientists at Scripps Research target estrogen-sensitive breast cancer cells in new ways, potentially creating better options for patients with treatment-resistant cancers. More information on these dual-mechanism estrogen receptor inhibitors was published by Min et al in the Proceedings of the National Academy of Sciences.

“Hormone therapies for breast cancer have been one of the greatest success stories of molecularly targeted medicines. But a significant fraction of patients don’t respond to these therapies,” said lead study author Kendall Nettles, PhD, Associate Professor of Integrative Structural and Computational Biology at the Scripps Research Florida campus. “There’s a continued unmet medical need for better hormone therapies. This represents the first change in approach in 20 years.”

Drugs like tamoxifen, fulvestrant, or anastrozole are frequently prescribed for estrogen-sensitive breast cancers. But over time, some breast cancers can develop resistance, through inflammatory processes and through expression of resistance genes including EGFR.

The compounds developed by Dr. Nettles and colleagues work by interfering with estrogen’s ability to activate its cellular receptor in the traditional way, as seen with the hormone therapy tamoxifen, but also by a second inhibitory mechanism. Tests in cells showed greater efficacy in the presence of drug-resistance mechanisms, Dr. Nettles explained.

Kendall Nettles, PhD

Kendall Nettles, PhD

Estrogen and Breast Cancer

Seven out of 10 breast cancers are sensitive to estrogen. The hormone promotes cancer growth by activating receptors on the cell surface. When touched, they send chemical signals into the cell nucleus that lead key growth and proliferation genes to march into action.

That’s why doctors treat estrogen-sensitive cancers by either suppressing estrogen production or interfering with estrogen’s ability to bind those receptors. If the cell can’t receive the signal, the estrogen won’t activate more tumor growth. However, shutting off all of estrogen’s activity may lead to menopause-related side effects, including osteoporosis and hot flashes.

Depending on a patient with breast cancer’s age and menopausal status, doctors will prescribe either a group of medicines called selective estrogen receptor modulators (SERMs), such as tamoxifen, or selective estrogen receptor downregulators (SERDs) such as fulvestrant.

At a molecular and structural level, those drugs interact with the pocket where estrogen binds and use a single, carefully positioned side chain to block the receptor’s growth-promoting activity.

Current Study Findings

Working with colleagues from Scripps Research and the University of Illinois at Urbana-Champaign, Dr. Nettles’ team designed the set of compounds to interfere with estrogen binding via distortion of the estrogen receptor binding pocket and binding with two different molecular side chains.

Their studies showed the compounds acted either as estrogen receptor downregulators or, much like tamoxifen, as selective estrogen receptor modulators. Their two different side chains can be altered in a variety of ways to influence potency and manage side effects, Dr. Nettles said.

Chemist John Katzenellenbogen, PhD, built the molecules in Illinois, while in Florida, Tina Izard, PhD, at Scripps Research oversaw x-ray crystallography studies that revealed the molecules’ structure and Pat Griffin, PhD, oversaw hydrogen-deuterium mass spectrometry studies that enabled studies of the compounds’ effect on estrogen receptors. Those studies showed the compounds destabilized or repositioned the receptor shape, allowing for a different method of direct binding.

One-third of women with early-stage breast cancer treated with tamoxifen developed resistance to the drug within 2 to 5 years, a recent study found. The new compounds are urgently needed, Dr. Nettles said.

Next steps include testing the compounds in mouse models of breast cancer and tweaking the molecules to enhance their drug-like properties, such as staying in the bloodstream for the appropriate length of time. Most investigational drugs fail endpoints before reaching the clinic, but Dr. Nettles is optimistic about the compounds’ path forward.

“We’re hopeful this could be a breakthrough for treatment-resistant breast cancer,” he concluded. “With a new mechanism of action, the compounds do what you could expect from combining two different drugs, but in one molecule.”

Disclosure: Support for the research came from the National Institutes of Health, the Breast Cancer Research Foundation, Shengjing Hospital of China Medical University, and Frenchman’s Creek Women for Scripps Research. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.