By Gabriel Paijo 
In a major development for the field of oncology, researchers at the MUSC Hollings Cancer Center have unveiled a novel therapeutic approach aimed at one of the most lethal and elusive forms of the disease: triple-negative breast cancer (TNBC). Published recently in the journal Breast Cancer Research, the study details the development and successful preclinical testing of a humanized monoclonal antibody designed to inhibit a specific protein that facilitates tumor growth and suppresses the body’s natural immune defenses. This breakthrough not only offers a potential new treatment path for patients who have exhausted standard options but also provides a deeper understanding of how the immune system can be "reprogrammed" to fight aggressive malignancies.
The Unique Challenge of Triple-Negative Breast Cancer
Triple-negative breast cancer accounts for approximately 10% to 15% of all breast cancer cases, yet it remains disproportionately responsible for cancer-related deaths due to its aggressive nature. Unlike other subtypes of breast cancer, TNBC lacks the three most common receptors known to fuel most breast cancer growth: estrogen receptors (ER), progesterone receptors (PR), and the human epidermal growth factor receptor 2 (HER2).
Because these receptors are absent, traditional targeted therapies—such as hormone therapy or drugs like Herceptin—are ineffective. Consequently, the primary treatment for TNBC has historically been limited to surgery, radiation, and systemic chemotherapy. While many patients initially respond well to chemotherapy, the recurrence rate is high. When the cancer returns, it is often metastatic and significantly more resistant to existing drugs, leaving clinicians with few effective tools to combat the disease.
The research led by Nancy Klauber-DeMore, M.D., a breast surgical oncologist and co-leader of the Developmental Cancer Therapeutics Research Program at Hollings, addresses this therapeutic vacuum. By identifying a new molecular target, the team hopes to move beyond the limitations of traditional cytotoxic treatments.
Identifying the SFRP2 Protein: A Twenty-Year Journey
The centerpiece of this research is a protein known as secreted frizzled-related protein 2 (SFRP2). The discovery of SFRP2’s role in cancer is the result of nearly two decades of investigation. Dr. Klauber-DeMore’s laboratory first identified the protein’s involvement in breast cancer in 2008, noting its presence in the vasculature of tumors.
SFRP2 is a multi-functional protein that tumors utilize to create a favorable environment for survival. It promotes angiogenesis—the formation of new blood vessels that "feed" the tumor with oxygen and nutrients. Furthermore, it acts as a survival factor for cancer cells, preventing apoptosis (programmed cell death) even when the cells are under stress from chemotherapy. Perhaps most critically, the protein has been found to play a pivotal role in "immune exhaustion," a state where the body’s immune cells are present near the tumor but are rendered inactive or suppressed.
"My lab first identified the role of SFRP2 in breast cancer in 2008," Klauber-DeMore stated. "Since then, we’ve discovered its mechanism of action in breast cancer growth, metastasis, and immune exhaustion and developed an antibody to block SFRP2."
To target this protein, the MUSC team developed a humanized monoclonal antibody. Unlike mouse-derived antibodies, humanized antibodies are engineered to be more compatible with the human immune system, reducing the likelihood of an adverse immune reaction against the drug itself while maintaining high precision in binding to the target protein.
Reprogramming the Tumor Microenvironment: M1 vs. M2 Macrophages
One of the most significant findings of the study involves the "reprogramming" of the tumor microenvironment. The researchers discovered that SFRP2 is expressed not just by the cancer cells themselves, but also by the surrounding immune cells, specifically tumor-associated macrophages (TAMs).
In the complex ecosystem of a tumor, macrophages—a type of white blood cell—can exist in two primary states. M1 macrophages are considered "pro-inflammatory" and are essential for identifying and destroying cancer cells. Conversely, M2 macrophages are "anti-inflammatory" and are often co-opted by the tumor to help it grow, spread, and hide from the rest of the immune system. In aggressive cancers like TNBC, the ratio typically shifts heavily toward the "bad" M2 state.
The MUSC study demonstrated for the first time that SFRP2 is expressed on these macrophages. When the experimental antibody was administered, it triggered a significant shift in the macrophage population. The treatment stimulated the release of interferon-gamma, a critical signaling molecule that pushed the macrophages from the tumor-promoting M2 state back into the cancer-fighting M1 state.
Lillian Hsu, M.D., an MUSC surgical resident and key member of the research team, highlighted the clinical importance of this mechanism. "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 explained. This distinction is vital, as systemic administration of cytokines like interferon-gamma can cause severe flu-like symptoms and organ toxicity in patients.
Furthermore, the antibody was found to revitalize T-cells—the "infantry" of the immune system. In advanced TNBC, T-cells often become "exhausted," losing their ability to kill cancer cells. The SFRP2 antibody treatment restored T-cell activity, suggesting that this therapy could potentially be used in combination with existing immunotherapies, such as checkpoint inhibitors, to improve overall response rates.
Combating Metastasis and Chemotherapy Resistance
The study utilized two distinct models of advanced TNBC to test the antibody’s efficacy. In both models, the results were consistent: mice treated with the SFRP2 antibody showed a significant reduction in the growth of primary tumors and, more importantly, a dramatic decrease in lung metastasis.
Metastasis—the spread of cancer to distant organs—is the leading cause of death in breast cancer patients. When TNBC spreads to the lungs, the prognosis becomes particularly grim. By blocking SFRP2, the researchers were able to interrupt the signaling pathways that allow cancer cells to break away from the primary tumor and survive in the bloodstream.
Perhaps the most encouraging aspect of the preclinical data involves chemotherapy resistance. The team tested the antibody against cancer cells that had been conditioned to survive doxorubicin, a standard but highly toxic chemotherapy agent often referred to as "the Red Devil." Even in these resistant cell lines, the SFRP2 antibody induced significant cell death.
"That’s a very encouraging finding," Klauber-DeMore said, "because it suggests the therapy may be effective even when standard treatments fail."
Precision Targeting and Safety Profile
A recurring issue with traditional cancer treatments is "off-target" effects, where the drug attacks healthy cells alongside cancerous ones, leading to debilitating side effects. The MUSC team utilized advanced tracking to see where the SFRP2 antibody traveled within the body.
The data showed that the antibody selectively accumulated within the tumor tissue. Critically, it did not build up in healthy organs or normal blood cells. This high level of specificity is a hallmark of precision medicine and suggests that the antibody may have a much more favorable safety profile than traditional chemotherapy. Because SFRP2 is highly expressed in the "neighborhood" of the tumor but not in healthy tissues, the antibody acts like a heat-seeking missile, sparing the rest of the body from unnecessary damage.
Chronology of Development and Path to Clinical Trials
The development of this antibody represents a long-term commitment to translational research at MUSC. Following the initial 2008 discovery, the timeline involved:
- 2008–2015: Mapping the molecular pathways of SFRP2 in angiogenesis and tumor growth.
- 2016–2020: Engineering the humanized monoclonal antibody and conducting initial in vitro tests.
- 2021–2023: Extensive preclinical testing in mouse models of TNBC and studying the immune microenvironment.
- 2024: Publication of the findings in Breast Cancer Research and securing FDA designations.
The antibody has been licensed to Innova Therapeutics, a biotechnology company based in Charleston, South Carolina. Dr. Klauber-DeMore, who co-founded the company, is currently working with the team to secure the necessary funding and regulatory approvals for a first-in-human clinical trial.
Notably, the therapy has already received attention from the U.S. Food and Drug Administration (FDA) for other applications. It has been granted Rare Pediatric Disease and Orphan Disease designations for the treatment of osteosarcoma, a rare and aggressive bone cancer that also heavily expresses the SFRP2 protein. While these designations do not yet allow for general patient use, they provide significant financial and regulatory incentives to accelerate the drug’s development.
Broader Implications for Oncology and Future Outlook
The implications of this research extend beyond triple-negative breast cancer. By identifying SFRP2 as a master regulator of the tumor microenvironment, the MUSC team has opened a door to treating other "cold" tumors—cancers that the immune system typically ignores or cannot penetrate.
If clinical trials prove successful, the SFRP2 antibody could represent a new pillar of cancer treatment. It functions not just by killing cancer cells directly, but by "re-engineering" the environment so that the body’s own defenses can resume their natural function. In an era where immunotherapy has transformed the treatment of cancers like melanoma and lung cancer, this research provides a much-needed roadmap for bringing those same benefits to breast cancer patients.
As the team prepares for the transition from the laboratory to the clinic, the focus remains on the patients who currently have the fewest options. "The preliminary data are really encouraging," Dr. Hsu concluded. "I feel grateful to have been part of research that could one day help so many patients."
With the backing of Innova Therapeutics and the momentum of successful preclinical trials, the hope is that this novel antibody will soon move into Phase I clinical trials, marking the next step in a twenty-year journey to turn a biological discovery into a life-saving medicine.
