MUSC Researchers Develop Novel Antibody Targeting SFRP2 to Combat Triple-Negative Breast Cancer Resistance
核心洞察
Researchers at MUSC Hollings Cancer Center (搜索) have developed an experimental antibody targeting secreted frizzled-related protein 2 (搜索) (SFRP2 (搜索)) that shows promise in overcoming treatment resistance in triple-negative breast cancer (搜索).
The antibody demonstrated ability to slow primary tumor growth, reduce lung metastases, and reprogram immune cells from cancer-promoting M2 macrophages to cancer-fighting M1 macrophages in preclinical studies.
Laboratory testing revealed the antibody remained effective against cancer cells resistant to doxorubicin chemotherapy, offering potential treatment options for patients with refractory disease.
Researchers at the MUSC Hollings Cancer Center (搜索) have developed a promising experimental antibody that targets a key protein involved in triple-negative breast cancer (搜索) (TNBC (搜索)) resistance mechanisms. The preclinical study, published in Breast Cancer Research, demonstrates the antibody's ability to slow tumor growth, reduce metastases, and overcome chemotherapy resistance while reprogramming the tumor immune microenvironment.
Targeting SFRP2 to Disrupt Multiple Cancer Survival Pathways
The research centers on secreted frizzled-related protein 2 (搜索) (SFRP2 (搜索)), a protein that enables tumors to thrive through multiple mechanisms including promoting new blood vessel formation, preventing cancer cell death, and weakening immune responses. Led by Dr. Nancy Klauber-DeMore, a breast surgical oncologist who co-leads the Developmental Cancer Therapeutics Research Program at Hollings, the work builds on nearly two decades of research since her lab first identified SFRP2's role in breast cancer in 2008.
"Since then, we've discovered its mechanism of action in breast cancer growth, metastasis and immune exhaustion and developed an antibody to block SFRP2 (搜索)," Klauber-DeMore said. The team developed a humanized monoclonal antibody engineered to precisely target SFRP2 and block its cancer-promoting effects.
Immune System Reprogramming Shows Promise
Analysis of human tumor samples revealed SFRP2 (搜索) expression not only in cancer cells but also in surrounding immune cells, including tumor-infiltrating lymphocytes and macrophages. "This is the first time anyone has demonstrated that SFRP2 is expressed on tumor-associated macrophages," Klauber-DeMore noted. "That finding alone opens up an entirely new way of understanding and potentially manipulating the immune microenvironment."
The antibody treatment induced a significant shift in macrophage polarization. In TNBC (搜索), macrophages typically adopt an M2 state that suppresses immune activity and supports tumor growth. After SFRP2 antibody (搜索) treatment, macrophages released large amounts of interferon-gamma, pushing them toward the cancer-fighting M1 state. This effect was observed even in mice with advanced disease and existing metastases.
"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 Dr. Lillian Hsu, a MUSC surgical resident involved in the research. The treatment also restored activity in T-cells, which often become exhausted and dysfunctional in TNBC (搜索).
Significant Reduction in Metastases and Chemotherapy Resistance
In two different models of advanced TNBC (搜索), mice treated with the antibody developed significantly fewer lung tumors compared to untreated controls. Lung metastases indicate cancer has entered the bloodstream and correlate with worse patient outcomes. The antibody demonstrated precision targeting, accumulating in tumor tissue while sparing healthy organs and normal cells.
Addressing chemotherapy resistance, a major challenge in TNBC (搜索) treatment, the antibody remained effective against cancer cells that no longer responded to doxorubicin, a commonly used chemotherapy drug. "That's a very encouraging finding because it suggests the therapy may be effective even when standard treatments fail," Klauber-DeMore said.
Clinical Development and Regulatory Recognition
The antibody has been licensed to Innova Therapeutics (搜索), a Charleston-based biotechnology company co-founded by Klauber-DeMore, which is working to secure funding for a first-in-human clinical trial. The therapy has received Rare Pediatric Disease and Orphan Disease designations from the FDA for osteosarcoma (搜索), another cancer strongly linked to SFRP2 (搜索), providing development incentives while additional studies continue.
"Our hope 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," Klauber-DeMore said. The widespread presence of SFRP2 (搜索) throughout the tumor environment suggests targeting this protein could simultaneously weaken tumors, boost immune activity, and bypass treatment resistance.