Abstract
Triple-negative breast cancer (TNBC) is a heterogeneous disease in which the tumors do not express estrogen receptor (ER), progesterone receptor (PgR) or human epidermal growth factor receptor 2 (HER2). Classical receptor-targeted therapies such as tamoxifen or trastuzumab are therefore unsuitable and combinations of surgery, chemotherapy and/or radiotherapy are required. Photoimmunotheranostics is a minimally invasive approach in which antibodies deliver nontoxic photosensitizers that emit light to facilitate diagnosis and produce cytotoxic reactive oxygen species to induce apoptosis and/or necrosis in cancer cells. We developed a panel of photoimmunotheranostic agents against three TNBC-associated cell surface antigens. Antibodies against epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM) and chondroitin sulfate proteoglycan 4 (CSPG4) were conjugated to the highly potent near-infrared imaging agent/photosensitizer IRDye®700DX phthalocyanine using SNAP-tag technology achieving clear imaging in both breast cancer cell lines and human biopsies and highly potent phototherapeutic activity with IC50values of 62–165 nM against five different cell lines expressing different levels of EGFR, EpCAM and CSPG4. A combination of all three reagents increased the therapeutic activity against TNBC cells by up to 40%.
Highlights
Despite recent reduction in breast cancer mortality, breast cancer remains the leading cause of women’s cancer death worldwide [1]
Antibodies against epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM) and chondroitin sulfate proteoglycan 4 (CSPG4) were conjugated to the highly potent near-infrared imaging agent/photosensitizer IRDye®700DX phthalocyanine using SNAP-tag technology achieving clear imaging in both breast cancer cell lines and human biopsies and highly potent phototherapeutic activity with IC50 values of 62–165 nM against five different cell lines expressing different levels of EGFR, EpCAM and CSPG4
We have developed photoimmunotheranostic agents against three receptors that are strongly expressed in Triple-negative breast cancer (TNBC): the epidermal growth factor receptor (EGFR), the epithelial cell adhesion molecule (EpCAM) and chondroitin sulfate proteoglycan 4 (CSPG4) known as melanoma-associated chondroitin sulfate proteoglycan (MCSP) [19,20,21]
Summary
Despite recent reduction in breast cancer mortality, breast cancer remains the leading cause of women’s cancer death worldwide [1]. The molecular basis of breast cancer is well understood and five molecular subtypes are recognized: luminal A and B, HER2+, basal-like and normal breast-like [2]. Targeted therapies that rely on the expression of the estrogen receptor (ER), progesterone receptor (PgR) and epidermal growth factor receptor 2 (HER2) are effective treatments for luminal and HER2+ breast cancers [3]. Triple-negative breast cancer (TNBC) is a heterogeneous disease characterized by the absence of ER, PgR and HER2, and up to six distinct biological subgroups are reported. TNBC is more common in premenopausal patients, accounting for up to 20% of breast cancer cases [4]. TNBC patients do not benefit from drugs such as tamoxifen, aromatase inhibitors, trastuzumab, pertuzumab, trastuzumab-emtansin (TDM- 1) or palbociclib, which target the absent receptors.
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