By Gabriel Paijo 
Researchers at the MUSC Hollings Cancer Center have announced a significant breakthrough in the treatment of triple-negative breast cancer (TNBC), an aggressive and often recalcitrant form of the disease. By developing a specialized humanized monoclonal antibody that targets the secreted frizzled-related protein 2 (SFRP2), the multidisciplinary team has demonstrated a tripartite success in preclinical models: slowing primary tumor growth, significantly reducing metastatic spread to the lungs, and rejuvenating the immune system’s natural ability to identify and destroy malignant cells. This research, recently published in the journal Breast Cancer Research, offers a potential lifeline for patients who have exhausted traditional treatment options, particularly those whose cancers have developed resistance to standard chemotherapy.
The Clinical Challenge of Triple-Negative Breast Cancer
Triple-negative breast cancer accounts for approximately 10% to 15% of all breast cancer diagnoses but is responsible for a disproportionate number of deaths. The "triple-negative" designation refers to the fact that these cancer cells lack the three most common receptors known to fuel most breast cancer growth: estrogen receptors, progesterone receptors, and the human epidermal growth factor receptor 2 (HER2) protein.
Because the cancer lacks these receptors, common hormonal therapies and HER2-targeted drugs are ineffective. This leaves patients with a limited toolkit of treatments, primarily consisting of surgery, radiation, and cytotoxic chemotherapy. While TNBC often responds well to initial chemotherapy, it is notorious for its high rate of recurrence. When the cancer returns, it frequently does so with acquired resistance to the very drugs used to treat it initially, leading to a much poorer prognosis. Furthermore, TNBC is characterized by a high propensity for early metastasis, frequently spreading to the lungs, brain, and bones before the primary tumor is even detected.
A Two-Decade Quest: The SFRP2 Discovery Chronology
The development of the SFRP2-targeting antibody is the culmination of nearly 20 years of rigorous investigation led by Nancy Klauber-DeMore, M.D., a breast surgical oncologist and co-leader of the Developmental Cancer Therapeutics Research Program at MUSC Hollings Cancer Center. The timeline of this discovery reflects the slow and steady march of translational medicine, moving from basic protein identification to the engineering of a therapeutic agent.
In 2008, Dr. Klauber-DeMore’s laboratory first identified SFRP2 as a critical protein in the context of breast cancer. While SFRP proteins were historically thought to be inhibitors of the Wnt signaling pathway—a key regulator of cell growth—Klauber-DeMore’s research revealed that in the specific environment of a tumor, SFRP2 actually functions as a potent enabler of malignancy.
Over the subsequent decade, the team mapped the protein’s mechanism of action. They discovered that SFRP2 is a multi-functional "oncomodulator" that promotes angiogenesis (the formation of new blood vessels that feed the tumor), protects cancer cells from programmed cell death (apoptosis), and induces immune exhaustion. This comprehensive understanding of the protein’s role led to the eventual engineering of a humanized monoclonal antibody designed to bind specifically to SFRP2 and neutralize its effects.
The most recent phase of research involved a collaborative effort across several departments at MUSC, including Surgery, Biochemistry and Molecular Biology, and Pathology and Laboratory Medicine. Key contributors included surgical residents Lillian Hsu, M.D., and Julie Siegel, M.D., who helped execute the complex preclinical models required to validate the antibody’s efficacy.
Reprogramming the Tumor Microenvironment
One of the most significant findings of the new study is the antibody’s ability to re-engineer the tumor microenvironment (TME). Traditionally, cancer research has focused almost exclusively on killing the cancer cells themselves. However, modern oncology increasingly recognizes that the "neighborhood" surrounding the tumor—consisting of blood vessels, signaling molecules, and immune cells—is just as important.
The MUSC team discovered that SFRP2 is not only expressed by the cancer cells but is also highly prevalent on tumor-associated macrophages (TAMs). Macrophages are white blood cells that are supposed to "eat" pathogens and cellular debris. In a healthy state, "M1" macrophages stimulate the immune system to fight threats. However, tumors often hijack these cells, converting them into "M2" macrophages that suppress the immune response and help the tumor grow.
"This is the first time anyone has demonstrated that SFRP2 is expressed on tumor-associated macrophages," Dr. Klauber-DeMore noted. This discovery explains why TNBC is so effective at evading the immune system. The SFRP2 protein essentially acts as a chemical "cloak," turning the body’s defenders into unwitting accomplices.
When the experimental antibody was introduced in preclinical models, the researchers observed a dramatic shift. The antibody blocked SFRP2, causing the macrophages to release high levels of interferon-gamma. This signaling molecule pushed the macrophages back into the "good" M1 state. Simultaneously, the treatment revived "exhausted" T-cells—the specialized soldiers of the immune system—which had previously stopped functioning due to the tumor’s inhibitory signals.
Precision Targeting and the Reduction of Metastasis
A perennial challenge in oncology is the "off-target" effect, where chemotherapy kills healthy cells along with cancerous ones, leading to debilitating side effects like hair loss, nausea, and immune suppression. The SFRP2 antibody demonstrated a remarkable level of precision.
Using biodistribution studies, the researchers tracked the antibody as it moved through the body. They found that it accumulated almost exclusively within the tumor tissue. It did not build up in healthy organs, nor did it attach to healthy blood cells. This high specificity suggests that the treatment could be far less toxic than traditional chemotherapy, providing a better quality of life for patients undergoing treatment.
In terms of efficacy, the results in advanced TNBC models were striking. Mice treated with the antibody showed significantly fewer lung metastases compared to the control group. Because lung metastasis is a leading cause of mortality in TNBC patients, the ability of this antibody to restrict the cancer’s spread to the bloodstream and distant organs represents a major clinical milestone.
Overcoming Chemotherapy Resistance
The study also addressed the looming shadow of chemoresistance. The researchers tested the antibody against TNBC cells that had been specifically engineered to be resistant to Doxorubicin (also known by the brand name Adriamycin). Doxorubicin is a cornerstone of TNBC treatment, but it is often limited by its cumulative toxicity to the heart and the eventual adaptation of the tumor.
The data showed that even when the cancer cells no longer responded to Doxorubicin, the SFRP2 antibody remained effective at inducing cell death. This suggests that the antibody operates through a biological pathway entirely distinct from traditional DNA-damaging agents. For a patient whose cancer has returned after a standard course of "Red Devil" chemotherapy (a common nickname for Doxorubicin), this antibody could provide a vital secondary line of defense.
Broader Implications and Future Directions
The implications of this research extend beyond triple-negative breast cancer. The FDA has already granted the antibody Rare Pediatric Disease and Orphan Disease designations for osteosarcoma, a rare and aggressive bone cancer that also shows high levels of SFRP2 expression. These designations are intended to fast-track the development of drugs for conditions that have few existing treatment options.
Furthermore, the antibody’s ability to "warm up" what are known as "cold" tumors—cancers that the immune system normally ignores—suggests it could be used in combination with existing immunotherapies like PD-1 or PD-L1 inhibitors. Many TNBC patients do not currently respond to immunotherapy; by reprogramming the macrophages and reviving T-cells, the SFRP2 antibody may pave the way for these high-tech treatments to finally work.
The antibody has been licensed to Innova Therapeutics, a biotechnology firm based in Charleston, South Carolina. The company is currently focused on securing the necessary funding and regulatory approvals to initiate a first-in-human Phase I clinical trial.
While the transition from mouse models to human patients is always a rigorous and uncertain process, the MUSC Hollings Cancer Center team remains optimistic. The combination of reduced metastasis, immune system reactivation, and the ability to kill chemo-resistant cells makes the SFRP2 antibody a unique candidate in the crowded field of oncology research.
"Our hope," said Dr. Klauber-DeMore, "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." As the medical community looks toward a future of precision medicine, this research provides a robust framework for how targeting a single, multifaceted protein can disrupt the complex survival strategies of the world’s most aggressive cancers.