Can We Break Through Chemotherapy Resistance? A New Target for Triple-Negative Breast Cancer Appears

Among breast cancers, ‘triple-negative breast cancer (TNBC)’ is particularly challenging to treat. It lacks hormone receptors (HR) such as estrogen and progesterone, as well as the human epidermal growth factor receptor 2 (HER2), making it difficult to apply targeted therapies used for other types of breast cancer. The growth rate of cancer cells is also fast. Even if treatment seems effective initially, there are many cases where it recurs and becomes stronger.

A new target candidate that can simultaneously shake the ‘resilience (treatment resistance)’ of TNBC is gaining attention. A research team from the Medical University of South Carolina (MUSC) has developed a humanized monoclonal antibody targeting ‘SFRP2 (Secreted frizzled-related protein 2)’ and reported preclinical results that suppress tumor growth and metastasis while reviving immune responses. The research findings were published in the recent issue of the international journal Breast Cancer Research.

Reducing Lung Metastasis and Suppressing Tumor Growth… Even Resistant Cells ‘Die’

SFRP2 is described as a ‘helper’ that creates a favorable environment for tumors to survive. It promotes angiogenesis, opening up nutrient supply routes for tumors, inhibits apoptosis in cancer cells, making them harder to die, and alters the tumor microenvironment to exhaust immune cells (immune exhaustion). The paper presented that SFRP2 binds to the FZD5 (frizzled-5) receptor to activate signaling pathways involved in tumor growth and migration.

When the research team analyzed human TNBC tissues using multiplex immunostaining, SFRP2 was widely observed not only in cancer cells (87%) but also in tumor-associated macrophages (90%) and tumor-infiltrating lymphocytes (96%). This means it is not just a target aimed at the ‘tumor mass’ but also a clue that can shake the immune environment surrounding the tumor.

Tumor-associated macrophages can be broadly divided into two tendencies. One activates the immune system to attack cancer (M1), while the other suppresses immune responses and aids tumor growth (M2). In TNBC, macrophages tend to lean towards the M2 side, but when treated with the research team’s SFRP2 antibody, it was confirmed that macrophages secreted more interferon-gamma (IFN-γ) and signaled a return to the M1 tendency.

Animal model results are also notable. The research team reported that when the antibody was administered in TNBC preclinical models (E0771.LMB, PY8119), the number of lung metastatic nodules significantly decreased. In a human TNBC cell line (MDA-MB-231) xenograft model, tumor growth was suppressed by 61%. Most importantly, the possibility of ‘chemotherapy resistance,’ a common challenge in clinical settings, was also suggested. The results included that this antibody induced apoptosis in MDA-MB-231 cells that had developed resistance to the commonly used ‘doxorubicin’ in TNBC.

The research team also explained that the antibody showed a pattern of accumulating more selectively in tumor tissues while being relatively less distributed in normal organs. Unlike traditional chemotherapy that hits the whole body, the higher the precision of targeting, the more potential there is to reduce the burden of side effects.

Can We Catch Two Rabbits with ‘Targeted Therapy + Immune Redesign’?

The significance of this study is not limited to a single effect. Targeting SFRP2 allows for the simultaneous pursuit of ▲ tumor growth and metastasis suppression ▲ alleviation of immune-suppressive environments ▲ potential bypass of treatment resistance. While options such as immune checkpoint inhibitors and antibody-drug conjugates (ADCs) are expanding in TNBC treatment, the barriers of recurrence and resistance remain high.

However, the current stage is preclinical, before entering human clinical trials. There are many hurdles to overcome, including safety, appropriate dosing, and combination strategies.

According to the research team, this antibody has been licensed to the American biotech company ‘Innova Therapeutics,’ and funding for the first human trials and clinical preparations is underway. Additionally, the SFRP2-targeted antibody development program (project name IVT-8086) has received Rare Pediatric Disease designation and Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) related to pediatric osteosarcoma indications. Such ‘designations’ do not mean immediate use in patient treatment, but they serve as mechanisms to provide development incentives and support clinical entry.

*Source of the paper: Secreted frizzled-related protein 2 monoclonal antibody-mediated IFN-ϒ reprograms tumor-associated macrophages to suppress triple negative breast cancer. Breast Cancer Research, 2025; 27 (1) DOI: 10.1186/s13058-025-02176-6.