Research that originated in a Duke Cancer Institute (DCI) laboratory contributed to Food and Drug Administration (FDA) approval of the first new endocrine therapy for breast cancer since 2002, and the only drug designed to target mutations in estrogen receptor 1 (ESR1).
Donald McDonnell, PhD, associate director For translational research at DCI and the Glaxo-Wellcome Distinguished Professor of Molecular Cancer Biology, directed the research team that led to the development of elacestrant (Orserdu, Stemline Therapeutics, Inc).
The new therapy, a selective estrogen receptor down-regulator (SERD), is indicated for the treatment of postmenopausal women or adult men with estrogen-receptor-positive/HER2-negative ESR1-mutated advanced or metastatic breast cancer who have been treated unsuccessfully with at least one previous endocrine therapy.
The FDA approved the therapy in January 2023.
Meeting a Need
Erik Nelson
The drug is the only SERD that can be taken orally, which makes it more convenient for patients. McDonnell said it fills a significant unmet need because up to 40% of patients diagnosed with ER-positive/HER2-negative breast cancer will acquire ESR1 mutations as the cancer advances. In most cases, these mutations will trigger resistance to standard endocrine therapies.
During the past decade, the McDonnell Lab has been focused on identifying and developing new endocrine therapies to treat advanced ER-positive breast cancer. This initiative has included revisiting older hormone therapies originally developed to treat osteoporosis or menopause symptoms.
Elacestrant, for example, was developed initially to treat hot flashes in post-menopausal women but was never approved for that use. Clinical trials demonstrated that RAD1901, as the therapy was known, stopped hot flashes at low doses but increased them at higher doses. McDonnell and researchers in his lab were intrigued by the pharmacology. “It turns out that the reason for RAD1901’s failure as a treatment for hot flashes was a useful property for a breast cancer drug,” McDonnell said.
Investigators who were trainees in the McDonnell Lab at the time, Suzanne E. Wardell, PhD, and Erik Nelson, PhD, determined that RAD1901 was effective at blocking the estrogen driving cancer cell growth by binding to its receptor, like a selective estrogen receptor modulator(SERM), and degrading the estrogen receptor, like a SERD.
Wardell and Nelson went on to demonstrate that RAD1901 inhibited tumor growth in mouse models. This was the springboard for continued investigations worldwide; culminating in the successful multicenter phase 3 clinical trial (EMERALD 2018–2022) that led to FDA approval. Wardell is now an assistant professor of pharmacology and cancer biology at Duke, in McDonnell’s lab. Nelson is now a professor of molecular and integrative physiology at the University of Illinois Urbana-Champaign.
“We’re already prescribing elacestrant for our patients,” said Heather Moore, CPP, PharmD, a clinical pharmacist with Duke Health, noting that the drug is currently being distributed nationally by two specialty pharmacies.
Multiple myeloma remains one of the most challenging hematologic malignancies to treat. Despite advances in therapy, many patients eventually relapse or develop resistance to standard treatments.A team led by Mikhail Nikiforov, PhD, professor in the Duke University School of Medicine Department of Pathology and Biomedical Engineering, and Duke Cancer Institute member, is uncovering a promising new approach that could reshape the therapeutic landscape.Multiple myeloma is characterized by uncontrolled proliferation of plasma cells, which produce large amounts of dysfunctional antibodies. These abnormal proteins can damage organs such as the kidneys and weaken bones, leading to pain and fractures.The disease environment in the bone marrow is rich in iron, a nutrient essential for cell growth and DNA synthesis. Cancer cells exploit this iron abundance to fuel their rapid proliferation.However, excess iron can also trigger a unique form of cell death called ferroptosis, driven by oxidative damage to cell membranes.“Ferroptosis is a programmed death caused by iron-dependent lipid peroxidation, and it’s particularly relevant in iron-loaded environments like the bone marrow,” Nikiforov said.Nikiforov’s team focused on why some myeloma cells resist ferroptosis. Using genetic screening, they identified a kinase called STK17B as a key player. High levels of STK17B not only suppress ferroptosis but also correlate with poor patient survival and resistance to bortezomib, a cornerstone drug in myeloma therapy.“This kinase appears to help cancer cells maintain iron balance and avoid ferroptotic death,” Nikiforov said. “When we inhibit STK17B, iron overload tips the scale, and the cells die.”The team collaborated with Timothy Willson, PhD, Harold Kohn distinguished professor in open science drug discovery at the University of North Carolina Eshelman School of Pharmacy, who had previously developed an STK17B inhibitor. Using an improved formulation, they tested the compound in two myeloma models and observed significant efficacy.The findings were strong enough to warrant a provisional patent and open the door for future drug development. Currently, no FDA-approved therapies specifically induce ferroptosis.“Our work suggests a new therapeutic angle—targeting iron addiction in cancer cells,” Nikiforov said. “It could complement existing treatments and potentially apply to other iron-rich tumors.”Future research will explore combination strategies with standard therapies and immune-based approaches, as well as whether ferroptosis-targeting drugs could benefit other cancer treatments. The team is also investigating what regulates STK17B activity, aiming to uncover additional intervention points.“We’re excited about the possibilities,” Nikiforov said. “It’s early, but the data are compelling.”
Multiple myeloma remains one of the most challenging hematologic malignancies to treat. Despite advances in therapy, many patients eventually relapse or develop resistance to standard treatments.A team led by Mikhail Nikiforov, PhD, professor in the Duke University School of Medicine Department of Pathology and Biomedical Engineering, and Duke Cancer Institute member, is uncovering a promising new approach that could reshape the therapeutic landscape.Multiple myeloma is characterized by uncontrolled proliferation of plasma cells, which produce large amounts of dysfunctional antibodies. These abnormal proteins can damage organs such as the kidneys and weaken bones, leading to pain and fractures.The disease environment in the bone marrow is rich in iron, a nutrient essential for cell growth and DNA synthesis. Cancer cells exploit this iron abundance to fuel their rapid proliferation.However, excess iron can also trigger a unique form of cell death called ferroptosis, driven by oxidative damage to cell membranes.“Ferroptosis is a programmed death caused by iron-dependent lipid peroxidation, and it’s particularly relevant in iron-loaded environments like the bone marrow,” Nikiforov said.Nikiforov’s team focused on why some myeloma cells resist ferroptosis. Using genetic screening, they identified a kinase called STK17B as a key player. High levels of STK17B not only suppress ferroptosis but also correlate with poor patient survival and resistance to bortezomib, a cornerstone drug in myeloma therapy.“This kinase appears to help cancer cells maintain iron balance and avoid ferroptotic death,” Nikiforov said. “When we inhibit STK17B, iron overload tips the scale, and the cells die.”The team collaborated with Timothy Willson, PhD, Harold Kohn distinguished professor in open science drug discovery at the University of North Carolina Eshelman School of Pharmacy, who had previously developed an STK17B inhibitor. Using an improved formulation, they tested the compound in two myeloma models and observed significant efficacy.The findings were strong enough to warrant a provisional patent and open the door for future drug development. Currently, no FDA-approved therapies specifically induce ferroptosis.“Our work suggests a new therapeutic angle—targeting iron addiction in cancer cells,” Nikiforov said. “It could complement existing treatments and potentially apply to other iron-rich tumors.”Future research will explore combination strategies with standard therapies and immune-based approaches, as well as whether ferroptosis-targeting drugs could benefit other cancer treatments. The team is also investigating what regulates STK17B activity, aiming to uncover additional intervention points.“We’re excited about the possibilities,” Nikiforov said. “It’s early, but the data are compelling.”
