First-in-human response of BCL-2 inhibitor venetoclax in T-cell prolymphocytic leukemia
| Autor: | Georg Hopfinger, Marie-Bernadette Aretin, Christoph Kornauth, Nicole Prutsch, Philipp B. Staber, Bernadette Hilgarth, Ulrich Jäger, Emiel van der Kouwe, Sinan Gültekin, Ingrid Simonitsch-Klupp, Stefan Kubicek, Lukas Kazianka, Peter Valent, Gregor Hoermann, Marius E. Mayerhoefer, Lukas Kenner, Alexander W. Hauswirth, Olaf Merkel, Richard Moriggl, Wolfgang R. Sperr, Bernd Boidol, Michael Panny |
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| Rok vydání: | 2017 |
| Předmět: |
Adult
Male 0301 basic medicine Myeloid Immunology Drug Evaluation Preclinical Antineoplastic Agents Pharmacology Biology Biochemistry 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Recurrence Inside BLOOD Commentary Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols medicine Humans Neoplasm Molecular Targeted Therapy Prolymphocytic leukemia Sulfonamides Dose-Response Relationship Drug Venetoclax Cell Biology Hematology Middle Aged Bridged Bicyclo Compounds Heterocyclic medicine.disease High-Throughput Screening Assays Lymphoma Leukemia Treatment Outcome 030104 developmental biology medicine.anatomical_structure Proto-Oncogene Proteins c-bcl-2 chemistry Drug Resistance Neoplasm 030220 oncology & carcinogenesis Leukemia Prolymphocytic T-Cell Cancer research T-cell prolymphocytic leukemia Female Ex vivo |
| Zdroj: | Blood. 130:2499-2503 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2017-05-785683 |
| Popis: | T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive T-lymphoid malignancy usually refractory to current treatment strategies and associated with short overall survival. By applying next-generation functional testing of primary patient-derived lymphoma cells using a library of 106 US Food and Drug Administration (FDA)-approved anticancer drugs or compounds currently in clinical development, we set out to identify novel effective treatments for T-PLL patients. We found that the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (ABT-199) demonstrated the strongest T-PLL-specific response when comparing individual ex vivo drug response in 86 patients with refractory hematologic malignancies. Mechanistically, responses to venetoclax correlated with protein expression of BCL-2 but not with expression of the BCL-2 family members myeloid cell leukemia 1 (MCL-1) and BCL-XL in lymphoma cells. BCL-2 expression was inversely correlated with the expression of MCL-1. Based on the ex vivo responses, venetoclax treatment was commenced in 2 late-stage refractory T-PLL patients resulting in clinical responses. Our findings demonstrate first evidence of single-agent activity of venetoclax both ex vivo and in humans, offering a novel agent in T-PLL. |
| Databáze: | OpenAIRE |
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