Protein-Protein Interactions could lead to new cancer treatments

Molecules being developed by Terry Moore could one day make a big impact on the lives of individuals fighting breast cancer.

Moore, PhD, University of Illinois Cancer Center member and assistant professor of medicinal chemistry and pharmacognosy in the UIC College of Pharmacy, is using a new method involving protein-protein interactions to target estrogen receptors that have become resistant to tamoxifen, a commonly used treatment for early and advanced estrogen receptor-positive breast cancer.

Breast cancer is the second leading cause of cancer death in women (only lung cancer kills more women each year). About one in eight women – 12.4 percent – will develop invasive breast cancer over the course of her lifetime, according to the American Cancer Society. About 266,120 new cases of invasive breast cancer will be diagnosed in women in 2018, with about 63,960 new cases of carcinoma in situ being identified. Approximately 40,920 women are expected to die from breast cancer this year.

When estrogen receptor-positive breast cancer becomes impervious to endocrine therapy drugs, which tamoxifen is, physicians have few treatment options left to offer patients, Moore said.

“Typically, when you think of resistance you think of mutations that might cause this action,” said Moore, a medicinal chemist. “Researchers have been searching for these alterations for decades, but they haven’t found them because they were always looking in the primary tumors. Many of these mutations are in distant metastases.”

Many researchers today are studying the estrogen binding site. Moore, however, is taking a different tact. Through the use of protein-protein interaction, he is developing molecules that can be used to its detriment.

“Approximately 30 to 40 percent of women who have metastatic estrogen receptor breast cancer have one of these mutations,” Moore said. “Our goal is to develop antagonists that work against these mutant estrogen receptors.”

Proteins rarely act alone, and their functions tend to be regulated. Moore’s laboratory is using the interaction between them by targeting the estrogen receptor at a different site through the use of “stapled peptides.” Molecules they have developed can bind to the mutant estrogen receptors. The stapled molecular structure causes the peptides to degrade at slower rates in the bloodstream, not unlike many small molecules, and more easily penetrate the cell to affect the function of the estrogen receptor.

The stapled peptides have successfully worked in biochemical models, and Moore and his colleagues are researching the inhibition of estrogen receptor-positive cancer growth using stapled peptides in vitro.

Moore is not limiting his discoveries using protein-protein interactions to treating cancer. He is also studying how the activation of the protein Nrf2, which protects against oxidative damage triggered by injury or inflammation, can be used to treat chronic wounds. Activating Nrf2 could be a useful therapeutic strategy in treating chronic skin wounds, which include, but are not limited to pressure sores, diabetic foot ulcers and venous ulcers. He received a R01 grant – his first – in 2017 from the National Institute of Health’s National Institute of Arthritis and Musculoskeletal and Skin Diseases to research his new concepts.

“More than 6.5 million Americans are affected by chronic wounds, with more than $25 billion spent annually to treat them,” Moore said. “Since there are no pharmaceutical products on the market to treat chronic wounds, we’re interested in creating a topical treatment that can be used to accelerate their healing. We want to create something new to help people.”

This has been a busy year for Moore, not only with his research, but also having published papers in ACS (American Chemical Society) Medicinal Chemistry Letters, Organic & Biomolecular Chemistry and ACS Chemical Biology.

After receiving a biochemistry degree from Abilene Christian University, Moore spent two years working for a biotechnology company in Boston before realizing he missed academia. He was accepted to the University of Illinois at Urbana-Champaign, where he received a PhD in chemistry. Prior to joining the faculty at UIC, he was a post-doctoral researcher at UIUC and Emory University, where his interest in cancer grew working in a Specialized Program of Research Excellence (SPORE) program.

“I’m extremely interested in hormone positive cancers, such as breast and prostate, because of their similarities,” Moore said. “I find the work to be very rewarding, especially at UIC, where we have a large medical center, because I’m interested in seeing patients. It brings an immediacy to your work. I enjoy being hands-on, because the patients are real people with real illnesses that need your help.”

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