Breast cancer research : BCR · 2025
Multi-receptor targeted therapy of breast cancer and brain metastases with a novel QUAD-drug conjugate.
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Debinski Waldemar, Fink Kaitlin N, Rossmeisl John, Mott Ryan T, Watabe Kounosuke, D'Agostino Ralph, Thomas Alexandra, Herpai Denise
Аннотация
BACKGROUND: Identifying treatments for triple-negative breast cancer (TNBC) remains a critical medical need. We have found that Interleukin 13 receptor alpha 2 (IL-13RA2), EphA2, EphA3 and EphB2 receptors are over-expressed collectively in majority of patients with breast cancer and its brain metastases. We are pursuing the novel idea of targeting these four tumor-associated receptors identified by us with one pharmaceutical compound. A compound, called QUAD, was designed and constructed, which binds all four targeted receptors.
METHODS: We have examined the presence of IL-13RA2, EphA2, EphA3 and EphB2 receptors in breast cancer cells in vitro, tissue micro-arrays including involved lymph nodes, and in paired primary tumor-brain metastases, including two subtypes of breast cancer. We also tested the activity of the quadrivalent ligand, QUAD, conjugated to a derivative of maytansine, DM1, in vitro and in vivo.
RESULTS: We have found that the four target receptors are frequently over-expressed in breast cancer, including TNBC and (HER2)-positive breast cancers and related metastases to the brain. This is based on the observed expression levels for the genes and the gene products; a combined expression of our target of interest approaches 100% of specimens' positivity. Furthermore, several TNBC cell lines were killed at low concentrations of QUAD-DM1 conjugate. MDA-MB-231 tumors growing in mammary pads of athymic mice responded significantly to a dose of 12 mg/kg (3x). MDA-MB-231-BrM tumors growing intracranially also responded to 4 µg/mouse (1x) of QUAD-DM1.
CONCLUSIONS: QUAD-DM1 is a novel multivalent drug conjugate that appears to be highly suitable for the treatment of breast cancer and related brain metastases. The drug candidate can be administered systemically, due to its favorable toxicity profile, or loco-regionally.
METHODS: We have examined the presence of IL-13RA2, EphA2, EphA3 and EphB2 receptors in breast cancer cells in vitro, tissue micro-arrays including involved lymph nodes, and in paired primary tumor-brain metastases, including two subtypes of breast cancer. We also tested the activity of the quadrivalent ligand, QUAD, conjugated to a derivative of maytansine, DM1, in vitro and in vivo.
RESULTS: We have found that the four target receptors are frequently over-expressed in breast cancer, including TNBC and (HER2)-positive breast cancers and related metastases to the brain. This is based on the observed expression levels for the genes and the gene products; a combined expression of our target of interest approaches 100% of specimens' positivity. Furthermore, several TNBC cell lines were killed at low concentrations of QUAD-DM1 conjugate. MDA-MB-231 tumors growing in mammary pads of athymic mice responded significantly to a dose of 12 mg/kg (3x). MDA-MB-231-BrM tumors growing intracranially also responded to 4 µg/mouse (1x) of QUAD-DM1.
CONCLUSIONS: QUAD-DM1 is a novel multivalent drug conjugate that appears to be highly suitable for the treatment of breast cancer and related brain metastases. The drug candidate can be administered systemically, due to its favorable toxicity profile, or loco-regionally.