Triple-negative breast cancer (TNBC), one of the most aggressive and hard-to-treat forms of breast cancer, may soon have a new therapeutic option. Researchers at the MUSC Hollings Cancer Center have developed an experimental antibody that targets a key protein helping TNBC tumors grow, spread and evade the immune system. Early findings, published in Breast Cancer Research, suggest the treatment could slow tumor growth, reduce metastasis and overcome resistance to chemotherapy.
TNBC accounts for a significant share of breast cancer deaths because it lacks the hormone receptors that allow many other breast cancers to be treated with targeted drugs. The disease tends to grow quickly, spread early and recur after initial treatment, often in a more treatment-resistant form.
In the new preclinical study, scientists tested a humanized monoclonal antibody designed to block secreted frizzled-related protein 2 (SFRP2), a molecule that supports tumor survival in multiple ways. SFRP2 promotes the formation of new blood vessels, prevents cancer cell death and weakens immune cells that would otherwise help eliminate tumors.
The research builds on nearly two decades of work led by Nancy Klauber-DeMore, M.D., a breast surgical oncologist and co-leader of the Developmental Cancer Therapeutics Research Program at Hollings. Her team first identified SFRP2’s role in breast cancer in 2008 and has since mapped how it drives tumor growth, metastasis and immune exhaustion.
“My lab first identified the role of SFRP2 in breast cancer in 2008,” Klauber-DeMore said. “Since then, we’ve discovered its mechanism of action in breast cancer growth, metastasis and immune exhaustion and developed an antibody to block SFRP2.”
The multidisciplinary team, which included researchers from MUSC’s Surgery, Biochemistry and Molecular Biology, and Pathology and Laboratory Medicine departments, found that the antibody produced several encouraging effects. In animal models, it slowed the growth of primary tumors, reduced the spread of cancer to the lungs and restored immune activity that is typically suppressed in TNBC. The therapy also killed cancer cells that no longer responded to doxorubicin, a commonly used chemotherapy drug.
Reprogramming the Immune Environment
To confirm SFRP2 as a viable target, researchers analyzed human TNBC samples and discovered that the protein was present not only in cancer cells but also in nearby immune cells, including tumor-infiltrating lymphocytes and tumor-associated macrophages.
“This is the first time anyone has demonstrated that SFRP2 is expressed on tumor-associated macrophages,” Klauber-DeMore said. “That finding alone opens up an entirely new way of understanding and potentially manipulating the immune microenvironment.”
Macrophages can exist in two main states: M1 macrophages, which stimulate immune responses against cancer, and M2 macrophages, which suppress immunity and support tumor growth. In TNBC, macrophages typically skew toward the M2 state. After treatment with the SFRP2 antibody, macrophages began releasing high levels of interferon-gamma, a signaling molecule that shifted them back toward the cancer-fighting M1 state.
Even in mice with advanced disease and existing metastases, the antibody improved the balance between M1 and M2 macrophages, suggesting it could help retrain the immune system even at later stages of cancer.
“We discovered that it pushes macrophages toward the ‘good’ M1 state — without the toxic effects you’d see if you gave interferon-gamma directly,” said Lillian Hsu, M.D., a surgical resident at MUSC who worked on the study. “TNBC is so hard to treat, and so many therapies come with serious toxicities, so finding a way to activate the immune system without adding new side effects is especially meaningful.”
The antibody also restored activity in T-cells, which often become exhausted and ineffective in TNBC. After treatment, nearby T-cells became more active, indicating the therapy could strengthen immune defenses and potentially enhance responses to existing immunotherapies.
Precision Targeting and Reduced Spread
In two separate models of advanced TNBC, mice treated with the antibody developed significantly fewer lung metastases than untreated animals. Lung tumors are a sign that cancer has entered the bloodstream and are associated with poorer outcomes in patients.
Equally notable was the antibody’s precision. Tracking studies showed that it accumulated in tumor tissue but not in healthy organs or normal cells. This targeted behavior contrasts with traditional chemotherapy, which affects many cell types and often causes severe side effects.
Overcoming Drug Resistance
One of the most promising findings was the antibody’s ability to kill cancer cells that had become resistant to doxorubicin. Chemotherapy resistance is a major obstacle in TNBC treatment, and tumors frequently adapt to evade standard drugs.
“That’s a very encouraging finding,” Klauber-DeMore said, “because it suggests the therapy may be effective even when standard treatments fail.”
Path Toward Clinical Use
The study showed that SFRP2 is abundant throughout the tumor environment, appearing in both cancer cells and surrounding immune cells. This widespread presence suggests that targeting SFRP2 could weaken tumors, boost immune activity and bypass treatment resistance simultaneously.
Importantly, SFRP2 did not accumulate in healthy blood or immune cells, a distinction that supports the antibody’s potential as a safer, more selective therapy.
The antibody has been licensed to Innova Therapeutics, a Charleston-based biotechnology company co-founded by Klauber-DeMore. The company is now working to secure funding for a first-in-human clinical trial. The therapy has also received Rare Pediatric Disease and Orphan Disease designations from the U.S. Food and Drug Administration (FDA) for osteosarcoma, another cancer strongly linked to SFRP2. While these designations do not yet permit patient use, they provide incentives to accelerate development.
“Our hope,” Klauber-DeMore said, “is that this will one day offer patients a new option — one that not only treats the cancer but also re-engineers the immune system’s ability to fight it.”
“The preliminary data are really encouraging,” Hsu added. “I feel grateful to have been part of research that could one day help so many patients.”
