Cell and molecular determinants of in vivo efficacy of the BH3 mimetic ABT-263 against pediatric acute lymphoblastic leukemia xenografts
| Autor: | Raushan T. Kurmasheva, Barbara Szymanska, Santi Suryani, Mark J. Cowley, Ingrid Boehm, Triona Ni Chonghaile, Warren Kaplan, Hernan Carol, Donya Moradi Manesh, Laura High, Luke Jones, Peter J. Houghton, Jean-Pierre Bourquin, Elise Tonna, Malcolm A. Smith, Chintanu Sarmah, Viktoras Frismantas, Catherine A. Billups, Richard B. Lock, Kathryn Evans, Beat Bornhauser, Anthony Letai |
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| Přispěvatelé: | University of Zurich |
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Cancer Research
Cell Apoptosis 610 Medicine & health Biology Article In vivo Gene expression medicine Humans MCL1 1306 Cancer Research RNA Messenger Child Regulation of gene expression Sulfonamides Aniline Compounds Mesenchymal stem cell Precursor Cell Lymphoblastic Leukemia-Lymphoma Xenograft Model Antitumor Assays Molecular biology In vitro Neoplasm Proteins Gene Expression Regulation Neoplastic Myeloid Cell Leukemia Sequence 1 Protein medicine.anatomical_structure Proto-Oncogene Proteins c-bcl-2 Oncology 10036 Medical Clinic Cancer research 2730 Oncology |
| Popis: | Purpose: Predictive biomarkers are required to identify patients who may benefit from the use of BH3 mimetics such as ABT-263. This study investigated the efficacy of ABT-263 against a panel of patient-derived pediatric acute lymphoblastic leukemia (ALL) xenografts and utilized cell and molecular approaches to identify biomarkers that predict in vivo ABT-263 sensitivity. Experimental Design: The in vivo efficacy of ABT-263 was tested against a panel of 31 patient-derived ALL xenografts composed of MLL-, BCP-, and T-ALL subtypes. Basal gene expression profiles of ALL xenografts were analyzed and confirmed by quantitative RT-PCR, protein expression and BH3 profiling. An in vitro coculture assay with immortalized human mesenchymal cells was utilized to build a predictive model of in vivo ABT-263 sensitivity. Results: ABT-263 demonstrated impressive activity against pediatric ALL xenografts, with 19 of 31 achieving objective responses. Among BCL2 family members, in vivo ABT-263 sensitivity correlated best with low MCL1 mRNA expression levels. BH3 profiling revealed that resistance to ABT-263 correlated with mitochondrial priming by NOXA peptide, suggesting a functional role for MCL1 protein. Using an in vitro coculture assay, a predictive model of in vivo ABT-263 sensitivity was built. Testing this model against 11 xenografts predicted in vivo ABT-263 responses with high sensitivity (50%) and specificity (100%). Conclusion: These results highlight the in vivo efficacy of ABT-263 against a broad range of pediatric ALL subtypes and shows that a combination of in vitro functional assays can be used to predict its in vivo efficacy. Clin Cancer Res; 20(17); 4520–31. ©2014 AACR. |
| Databáze: | OpenAIRE |
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