Sézary syndrome patient-derived models allow drug selection for personalized therapy

Gallardo Hernández, Fernando; Andrades, Evelyn; Iglesias, Arnau; González, Jessica; Solé, Laura; Guillén, Yolanda; Blanco Ares, Gonzalo, 1989-; Colomo Saperas, Luis Alberto; Gimeno Vázquez, Eva; Conde Estévez, David; Rodríguez, Eva; Bielsa-Marsol, Isabel; Iglesias Coma, Mar; Bellosillo Paricio, Beatriz; Pujol Vallverdú, Ramon Maria; Regueiro, José R.; Bigas Salvans, Anna; Espinosa Blay, Lluís

doi:http://dx.doi.org/10.1182/bloodadvances.2021006860

Sézary syndrome patient-derived models allow drug selection for personalized therapy

Citació

Gallardo F, Andrades E, Iglesias A, González J, Solé L, Guillén Y, Blanco G, Colomo L, Gimeno E, Conde D, Rodriguez E, Bielsa-Marso I, Iglesias M, Bellosillo B, Pujol RM, Regueiro JR, Bigas A, Espinosa L. Sézary syndrome patient-derived models allow drug selection for personalized therapy. Blood Adv. 2022 Jun 14;6(11):3410-21. DOI: 10.1182/bloodadvances.2021006860

Resum

Current therapeutic approaches for Sézary syndrome (SS) do not achieve a significant improvement in long-term survival of patients, and they are mainly focused on reducing blood tumor burden to improve quality of life. Eradication of SS is hindered by its genetic and molecular heterogeneity. Determining effective and personalized treatments for SS is urgently needed. The present work compiles the current methods for SS patient-derived xenograft (PDX) generation and management to provide new perspectives on treatment for patients with SS. Mononuclear cells were recovered by Ficoll gradient separation from fresh peripheral blood of patients with SS (N = 11). A selected panel of 26 compounds that are inhibitors of the main signaling pathways driving SS pathogenesis, including NF-kB, MAPK, histone deacetylase, mammalian target of rapamycin, or JAK/STAT, was used for in vitro drug sensitivity testing. SS cell viability was evaluated by using the CellTiter-Glo_3D Cell Viability Assay and flow cytometry analysis. We validated one positive hit using SS patient-derived Sézary cells xenotransplanted (PDX) into NOD-SCID-γ mice. In vitro data indicated that primary malignant SS cells all display different sensitivities against specific pathway inhibitors. In vivo validation using SS PDX mostly reproduced the responses to the histone deacetylase inhibitor panobinostat that were observed in vitro. Our investigations revealed the possibility of using high-throughput in vitro testing followed by PDX in vivo validation for selective targeting of SS tumor cells in a patient-specific manner.