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

Area of Science:

• Oncology
• Dermatology
• Pharmacology

Background:

• Current Sézary syndrome (SS) therapies offer limited long-term survival benefits, primarily managing symptoms.
• The genetic and molecular heterogeneity of SS poses a significant challenge to effective treatment and eradication.
• There is an urgent need for personalized and effective therapeutic strategies for SS patients.

Purpose of the Study:

• To compile methods for generating and managing Sézary syndrome patient-derived xenografts (PDX).
• To evaluate drug sensitivity of SS cells against various pathway inhibitors.
• To validate potential targeted therapies using in vitro and in vivo models.

Main Methods:

• Mononuclear cells from 11 SS patients were isolated using Ficoll gradient separation.
• In vitro drug sensitivity testing was performed on 26 compounds targeting key SS signaling pathways (NF-kB, MAPK, HDAC, mTOR, JAK/STAT).
• Cell viability was assessed using CellTiter-Glo_3D assay and flow cytometry; positive hits were validated in SS PDX models in NOD-SCID-γ mice.

Main Results:

• In vitro testing demonstrated differential sensitivity of SS cells to specific pathway inhibitors.
• In vivo validation in SS PDX models largely corroborated in vitro findings, particularly for the histone deacetylase inhibitor panobinostat.
• Patient-specific responses to targeted therapies were observed.

Conclusions:

• High-throughput in vitro drug screening followed by PDX in vivo validation offers a promising approach for patient-specific targeting of SS tumor cells.
• This strategy holds potential for developing more effective and personalized treatments for Sézary syndrome.
• Further research into PDX models can accelerate the development of novel therapeutic strategies for SS.