In collaboration with oncology professor Wei Xu, professors Lingjun Li and Weiping Tang are developing tools to tackle breast cancers that no longer respond to traditional therapies
By Jill Sakai
Three University of Wisconsin–Madison professors are developing new treatments for common drug-resistant forms of breast cancer, which currently have few treatment options and are associated with poor patient outcomes.
Wei Xu, the Marian A. Messerschmidt Professor in the School of Medicine and Public Health, is collaborating with co-investigators Lingjun Li and Weiping Tang, both professors in the Pharmaceutical Sciences Division of the School of Pharmacy. They received a nearly $1.6 million grant this year through the Congressionally Directed Medical Research Programs of the U.S. Department of Defense, which funds high-risk, high-reward biomedical research that has the potential to advance breakthrough treatments or technologies to improve patient care and clinical outcomes.
With the new grant, Xu, Li and Tang are working to develop new agents active against endocrine-resistant breast cancer. In the majority of breast cancers, estrogen receptors (ER) on the tumor cells are a major driver of their growth and spread. Patients with ER-positive cancers typically receive endocrine therapy, which can block production of the hormones or prevent tumor cells from responding to them. However, many patients become resistant to endocrine therapies, after which their treatment options are limited.
Acquired mutations in the estrogen receptor, especially one subtype called ER-alpha, are often found in metastatic breast cancer patients. Such mutations can lock ER-alpha in an active state that drives tumor growth even when the hormones are not present.
“Approximately 50 percent of responsive tumors eventually relapse due to the development of resistance. At that time, patients have to be treated with chemotherapy and some people respond, some don’t,” Xu says. “There is a pressing need to identify a new class of ER-alpha-targeting compounds for the treatment of recurrent ER-alpha-expressing breast cancer.”
The UW–Madison team is pursuing a strategy to target the problematic receptor protein directly and remove it from tumor cells, thus bypassing drug resistance mechanisms.
“Our goal is to discover a novel compound that could promote degradation of the mutant estrogen receptor,” Xu says. The researchers screened a natural products library for compounds that could degrade estrogen receptors and found Diptoindonesin G (Dip G), which is made in the bark of some tropical plants.
In early studies, the researchers found that Dip G significantly decreases ER-alpha protein levels and blocks ER-alpha cancer-promoting activity in breast cancer cells. It can also degrade ER receptors carrying the common mutations that lead to drug resistance. Importantly, it spares non-tumor breast cells, meaning it is likely to have fewer side effects than other treatments under development. (A few other selective estrogen receptor degraders are currently being tested in clinical trials, but so far all of them require unsafe doses or have worrying side effects.)
“This could revolutionize treatment regimens and eliminate the mortality associated with metastatic breast cancer.”
“Importantly, Dip G acts via a mechanism distinct from all known endocrine-therapy agents,” says Li, Vilas Distinguished Achievement Professor of Pharmaceutical Sciences and Chemistry and Charles Melbourne Johnson Distinguished Chair in Pharmaceutical Sciences. The Li Lab is using mass spectrometry approaches to study which proteins Dip G affects and how it changes their protein levels.
Designing molecular tools that can trigger selective degradation of disease-causing proteins is a specialty of Tang’s. Tang, Janis Apinis Professor in the Pharmaceutical Sciences Division and director of the School of Pharmacy’s Medicinal Chemistry Center, is synthesizing Dip G derivatives to explore relationships between chemical structure and activity, with the goal of producing more potent versions for drug development. Tang and Xu have filed a patent for using Dip G and its derivatives for treatment of ER-positive breast cancer.
The researchers envision developing these derivatives to be used as a second line of treatment for cancers that have developed resistance to endocrine therapy, offering a new hope for patients no longer helped by their initial treatments.
“We hope these compounds can be developed as next-generation drugs for targeting ER-positive breast cancer, including those with the ER-activating mutations,” Xu says. “This could revolutionize treatment regimens and eliminate the mortality associated with metastatic breast cancer.”