Preclinical evaluation of eltrombopag in a PDX model of myelodysplastic syndromes
| Autor: | Wolf-Karsten Hofmann, Arwin Mehralivand, Laurenz Steiner, Nanni Schmitt, Ahmed Jawhar, Cleo-Aron Weis, Stefanie Uhlig, Justine Danner, Vladimir Riabov, Ali Darwich, Qingyu Xu, Julia Obländer, Eva Altrock, Tobias Boch, Nadine Weimer, Florian Nolte, Antje Knaflic, Mohamad Jawhar, Alexander Streuer, Verena Haselmann, Daniel Nowak, Johann-Christoph Jann, Verena Nowak, Alexander Marx, Georgia Metzgeroth, Johanna Flach, Iris Palme |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Oncology
Agonist Male Cancer Research medicine.medical_specialty medicine.drug_class Eltrombopag Apoptosis Disease Mice SCID Benzoates Article chemistry.chemical_compound Mice Mice Inbred NOD Internal medicine hemic and lymphatic diseases medicine Tumor Cells Cultured Animals Humans Thrombopoiesis Cancer models Aged Cell Proliferation Thrombopoietin receptor Aged 80 and over business.industry Myelodysplastic syndromes Hematology Middle Aged medicine.disease Prognosis Xenograft Model Antitumor Assays Clinical trial medicine.anatomical_structure Hydrazines chemistry Preclinical research Myelodysplastic Syndromes Pyrazoles Female Bone marrow business Myelodysplastic syndrome |
| Zdroj: | Leukemia |
| ISSN: | 1476-5551 0887-6924 |
| Popis: | Preclinical research of myelodysplastic syndromes (MDSs) is hampered by a lack of feasible disease models. Previously, we have established a robust patient-derived xenograft (PDX) model for MDS. Here we demonstrate for the first time that this model is applicable as a preclinical platform to address pending clinical questions by interrogating the efficacy and safety of the thrombopoietin receptor agonist eltrombopag. Our preclinical study included n = 49 xenografts generated from n = 9 MDS patient samples. Substance efficacy was evidenced by FACS-based human platelet quantification and clonal bone marrow evolution was reconstructed by serial whole-exome sequencing of the PDX samples. In contrast to clinical trials in humans, this experimental setup allowed vehicle- and replicate-controlled analyses on a patient–individual level deciphering substance-specific effects from natural disease progression. We found that eltrombopag effectively stimulated thrombopoiesis in MDS PDX without adversely affecting the patients’ clonal composition. In conclusion, our MDS PDX model is a useful tool for testing new therapeutic concepts in MDS preceding clinical trials. |
| Databáze: | OpenAIRE |
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