Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2025
Patient-derived neuroblastoma models are sensitive to nucleolin-recognizing liposomal drugs.
СтатьяНазвание и аннотация: Перевод в очереди
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Bensa Veronica, Lopes-Cardoso Hugo, Ciampi Eleonora, Voronovska Anastasiya, Bianchi Giovanna, Soares-Gonçalves João Manuel, Morini Martina, Ardito Martina, Marino Gaia, Gualco Beatrice, Musso Roberta, Concetti Chiara, Mazzocco Katia, Gaggero Gabriele, Vellone Valerio Gaetano, Lasorsa Vito Alessandro, Capasso Mario, Cilli Michele, Amoroso Loredana, Fragola Martina, Conte Massimo, Ponzoni Mirco, Brignole Chiara, Moreira João Nuno, Pastorino Fabio
Аннотация
BACKGROUND: Neuroblastoma (NB) represents the most frequent and aggressive form of extracranial solid tumor in childhood, causing 15 % of cancer mortality. We recently demonstrated that cell surface nucleolin (NCL) represents a novel cellular target for preclinical therapy against NB cell lines.
METHODS: NB cells derived from i) infiltrated bone marrow (BM; 132 patients, 85 at onset, 47 relapsed/refractory); ii) NB tumor tissues from 11 relapsed/refractory NB patients; iii) murine generations of 9 patient-derived xenografts (PDX) were evaluated for cell surface NCL expression by flow cytometry and immunohistochemistry analyses. The antitumor efficacy of a liposomal formulation of doxorubicin (DXR) functionalized with the F3 peptide-recognizing NCL (F3-lipo[DXR]) was tested towards patient-derived multicellular tumor spheroids (MCTS) and PDX models of NB.
RESULTS: About 60 % of BM-infiltrating NB cells and NB cells derived from tumor biopsies, and about 80 % of NB cells derived from PDX expressed cell surface NCL. In vitro, F3-lipo[DXR] resulted significantly more effective in terms of reducing cell viability of all the patient-derived MCTS models used, compared to the untargeted liposomal formulation (lipo[DXR]). In the in vivo PDX models, F3-lipo[DXR] significantly delayed tumor growth, induced tumor cells apoptosis and partly reduced the tumor vasculature. Furthermore, in a PDX model harboring the ALK mutation p.F1174L, the administration of the anti-ALK inhibitor crizotinib significantly increased the antitumor efficacy of F3-lipo[DXR].
CONCLUSION: Our results confirm that cell surface NCL is a biomarker and a potential target for NB, paving the way for further investigations aimed at the future clinical translation of innovative combination strategies against NB.
METHODS: NB cells derived from i) infiltrated bone marrow (BM; 132 patients, 85 at onset, 47 relapsed/refractory); ii) NB tumor tissues from 11 relapsed/refractory NB patients; iii) murine generations of 9 patient-derived xenografts (PDX) were evaluated for cell surface NCL expression by flow cytometry and immunohistochemistry analyses. The antitumor efficacy of a liposomal formulation of doxorubicin (DXR) functionalized with the F3 peptide-recognizing NCL (F3-lipo[DXR]) was tested towards patient-derived multicellular tumor spheroids (MCTS) and PDX models of NB.
RESULTS: About 60 % of BM-infiltrating NB cells and NB cells derived from tumor biopsies, and about 80 % of NB cells derived from PDX expressed cell surface NCL. In vitro, F3-lipo[DXR] resulted significantly more effective in terms of reducing cell viability of all the patient-derived MCTS models used, compared to the untargeted liposomal formulation (lipo[DXR]). In the in vivo PDX models, F3-lipo[DXR] significantly delayed tumor growth, induced tumor cells apoptosis and partly reduced the tumor vasculature. Furthermore, in a PDX model harboring the ALK mutation p.F1174L, the administration of the anti-ALK inhibitor crizotinib significantly increased the antitumor efficacy of F3-lipo[DXR].
CONCLUSION: Our results confirm that cell surface NCL is a biomarker and a potential target for NB, paving the way for further investigations aimed at the future clinical translation of innovative combination strategies against NB.