A single center phase II study of ixazomib in patients with relapsed or refractory cutaneous or peripheral T-cell lymphomas
Autor: | Noah A. Brown, Alexandra C. Hristov, Ryan A. Wilcox, Tycel Phillips, Philip S. Boonstra, Avery Polk, Mark S. Kaminski, Nathanael G. Bailey, Tera Mayer, Sumana Devata |
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Rok vydání: | 2017 |
Předmět: |
Boron Compounds
Male 0301 basic medicine T cell medicine.medical_treatment Glycine GATA3 Transcription Factor Article Ixazomib 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cell Line Tumor Tumor Cells Cultured medicine Humans Protease Inhibitors Viability assay Aged Salvage Therapy Chemotherapy business.industry NF-kappa B Lymphoma T-Cell Peripheral Hematology Middle Aged medicine.disease Exceptional Responder Lymphoma T-Cell Cutaneous Lymphoma 030104 developmental biology medicine.anatomical_structure chemistry 030220 oncology & carcinogenesis Proteasome inhibitor Cancer research Female business Ex vivo medicine.drug |
Zdroj: | American Journal of Hematology. 92:1287-1294 |
ISSN: | 0361-8609 |
Popis: | The transcription factor GATA-3, highly expressed in many cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphomas (PTCL), confers resistance to chemotherapy in a cell-autonomous manner. As GATA-3 is transcriptionally regulated by NF-κB, we sought to determine the extent to which proteasomal inhibition impairs NF-κB activation and GATA-3 expression and cell viability in malignant T cells. Proteasome inhibition, NF-κB activity, GATA-3 expression, and cell viability were examined in patient-derived cell lines and primary T-cell lymphoma specimens ex vivo treated with the oral proteasome inhibitor ixazomib. Significant reductions in cell viability, NF-κB activation, and GATA-3 expression were observed preclinically in ixazomib-treated cells. Therefore, an investigator-initiated, single-center, phase II study with this agent in patients with relapsed/refractory CTCL/PTCL was conducted. Concordant with our preclinical observations, a significant reduction in NF-κB activation and GATA-3 expression was observed in an exceptional responder following one month of treatment with ixazomib. While ixazomib had limited activity in this small and heterogeneous cohort of patients, inhibition of the NF-κB/GATA-3 axis in a single exceptional responder suggests that ixazomib may have utility in appropriately selected patients or in combination with other agents. |
Databáze: | OpenAIRE |
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