Triple-negative breast cancer (TNBC) is one of the most aggressive and treatment-resistant forms of breast cancer. It grows quickly, spreads early and lacks the hormone receptors that make other breast cancers treatable with targeted therapies. Even when patients initially respond to treatment, the cancer often returns and is more resistant than before.
Researchers at MUSC Hollings Cancer Center have now reported on what they suggest is promising strategy to overcome the cancer’s resistance to treatment. The investigators developed an antibody targeting secreted frizzled-related protein 2 (SFRP2), a protein that acts as a cancer enabler, fueling tumor growth by supporting new blood vessels, blocking cell death and weakening immune cells that should attack the cancer.
Their preclinical study, including tests in mice, found that the anti-SFRP2 antibody blocks several of the ways that TNBC cells survive, grow and evade the immune system. In preclinical tests, the antibody suppressed primary tumor growth and the spread of cancer to the lungs, and reenergized cancer-fighting immune cells. It even killed cancer cells that had stopped responding to chemotherapy.
Research lead Nancy Klauber-DeMore, MD, a breast surgical oncologist who co-leads Hollings’ Developmental Cancer Therapeutics Research Program, is corresponding author of the team’s reported study in Breast Cancer Research, titled “Secreted frizzled-related protein 2 monoclonal antibody-mediated IFN-ϒ reprograms tumor-associated macrophages to suppress triple negative breast cancer.”
“There is a pressing need for efficacious therapy for metastatic triple-negative breast cancer (TNBC),” the authors wrote. Chemotherapy remains the primary treatment, and while immunotherapy is now also becoming a significant form of treatment, some TNBCs remain unresponsive to immunotherapy. The development of resistance to existing therapies is common, the team continued. “Secreted frizzled-related protein 2 (SFRP2) has emerged as a promising therapeutic target for breast cancer.”
The newly reported work builds on nearly two decades of research on SFRP2 by Klauber-DeMore, and brings together a broad multidisciplinary team across MUSC’s Surgical Oncology, Biochemistry and Molecular Biology, and Pathology and Laboratory Medicine departments. “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.”
For their latest published study, which was co-led by MUSC surgical resident Lillian Hsu, PhD, and former resident Julie Siegel, MD, the team tested a humanized monoclonal antibody—hSFRP2 mAb—a highly targeted molecule designed to attach to SFRP2 and inhibit its cancer-causing effects. “This study investigates a crucial question,” they wrote. “Can TNBC, resistant to standard chemotherapy agents like doxorubicin, respond to the humanized monoclonal antibody against SFRP2 (hSFRP2 mAb)?
To confirm that SFRP2 could be a useful target for TNBC and investigate the antibody’s role in treating it, the researchers first examined human triple-negative breast tumors. They found that SFRP2 was present not only in the tumor cells themselves but also in nearby immune cells, including tumor-infiltrating lymphocytes (TILs) as well as tumor-associated macrophages (TAMs). “SFRP2 was preferentially localized in tumor cells, TAMs, TILs, and B-cells,” they stated. “This is the first time anyone has demonstrated that SFRP2 is expressed on tumor-associated macrophages,” Klauber-DeMore commented. “That finding alone opens up an entirely new way of understanding and potentially manipulating the immune microenvironment.”
Macrophages can be broadly categorized into two types: M1 macrophages that activate the immune system to fight cancer and M2 macrophages that suppress immunity to help cancer grow. A higher M1/M2 ratio indicates a dominance pro-inflammatory M1-like TAMs, which boost T-cell immune responses to tumors and improve immunotherapy effectiveness,” the investigators explained. In TNBC, macrophages usually skew toward the M2 type. And, as the authors continued. “… a lower M1/M2 ratio suggests an increase in immunosuppressive M2-like TAMs, aiding tumor escape, weakening immune responses, and facilitating drug resistance.” Increasing the M1/M2 TAM ratio might represent a potential strategy to help tackle anticancer drug resistance.
The researchers found that, when treated with the SFRP2 antibody, the macrophages released a surge of interferon-gamma (IFN-ϒ), a key immune signal that pushed them toward the tumor-fighting M1 state. “IFN-ϒ is a crucial cytokine in the immune response,” the team noted. “It can activate macrophages to a more pro-inflammatory state (M1), which is associated with anti-tumor activity.”
The team’s experiments in addition found that in mice with cancer that had already spread, the hSFRP2 antibody still induced this favorable M1:M2 ratio, indicating that it could “retrain” the immune system to fight cancer even in advanced disease. “We discovered that it pushes macrophages toward the ‘good’ M1 state—without the toxic effects you’d see if you gave interferon-gamma directly,” Hsu said. “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 re-energized cancer-fighting T-cells, which often become exhausted and stop working effectively in TNBC. Once treated with the antibody, nearby T-cells became more active, suggesting that the treatment may strengthen immune responses that are often weakened in cancer and reduce the success of immunotherapy.
In two models of advanced TNBC, mice treated with the antibody developed far fewer lung tumors than those not treated with the antibody. Lung metastases signal that cancer has spread through the bloodstream and can make outcomes far worse for patients. “In the lungs of mice with TNBC lung metastases, there was an increase in the M1/M2 TAM ratio in mice treated with hSFRP2 mAb compared to control,” the researchers stated in their discussion.
Not only was the antibody effective—it was highly targeted. When the investigators tracked its movement in the body, they found that it concentrated in tumor tissue but not in healthy organs or normally growing cells. That precision contrasts with traditional chemotherapies, which kill cells more broadly and contribute to the problematic side effects that many patients experience during treatment. “This study demonstrated a specific biodistribution pattern for hSFRP2 mAb, showing a selective accumulation in tumor tissues while sparing normal organs,” the authors pointed out. “By avoiding non-targeted organs, hSFRP2 mAb minimizes toxicity to healthy tissues, enhancing the therapeutic index.”
Finally, the team tested whether the antibody could tackle resistance to chemotherapy, which represents one of the biggest hurdles in cancer treatment. Doxorubicin, a standard drug used for TNBC, often works at first, but many tumors eventually stop responding. After creating cancer cells that no longer responded to doxorubicin, the researchers found that the antibody still triggered strong cell death in these hard-to-treat cells. “That’s a very encouraging finding,” Klauber-DeMore said, “because it suggests the therapy may be effective even when standard treatments fail.”
This study revealed that SFRP2 is present at high levels in the tumor ecosystem, in both cancer cells and surrounding immune cells, including tumor-infiltrating lymphocytes and tumor-associated macrophages. That suggests the SFRP2 antibody could act on multiple fronts at once by weakening the tumor, strengthening the immune response and bypassing treatment resistance.
Equally important, SFRP2 did not accumulate in healthy blood or immune cells, unlike many other immune-related treatments. That opens the door to adapting the antibody as a potent cancer therapy that treats the disease while minimizing unwanted side effects. “Our findings emphasize the effectiveness and safety of a humanized monoclonal antibody, hSFRP2 mAb, in addressing primary and metastatic TNBC,” the authors wrote. “We illustrate that hSFRP2 mAb inhibits tumor growth and metastatic spread, triggering apoptosis in tumor metastases and chemotherapy-resistant TNBC tumors.”
By showing that SFRP2 sits at the crossroads of tumor growth, immune suppression and treatment resistance, the study lays the foundation for a new kind of precision therapy that could work alongside or enhance existing immunotherapies for TNBC. “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.”
While further research is needed, these early findings offer promise. “Collectively, these findings set the stage for further investigation of hSFRP2 mAb as a targeted therapy for triple-negative breast cancer, fostering optimism for enhanced treatment outcomes in the future.”
The antibody has been licensed to biotech Innova Therapeutics, which is co-founded by Klauber-DeMore, and is working to raise funds for a first-in-human clinical trial. The therapy has also received FDA Rare Pediatric Disease and Orphan Disease designations for osteosarcoma, another cancer in which SFRP2 plays a major role. The FDA designations provide incentives to support the drug’s development as it moves toward clinical trials. “The preliminary data are really encouraging,” Hsu said. “I feel grateful to have been part of research that could one day help so many patients.”
