TY - JOUR
T1 - Cell and molecular determinants of in vivo efficacy of the BH3 mimetic ABT-263 against pediatric acute lymphoblastic leukemia xenografts
AU - Suryani, Santi
AU - Carol, Hernan
AU - Chonghaile, Triona N.i.
AU - Frismantas, Viktoras
AU - Sarmah, Chintanu
AU - High, Laura
AU - Bornhauser, Beat
AU - Cowley, Mark J.
AU - Szymanska, Barbara
AU - Evans, Kathryn
AU - Boehm, Ingrid
AU - Tonna, Elise
AU - Jones, Luke
AU - Manesh, Donya M.oradi
AU - Kurmasheva, Raushan T.
AU - Billups, Catherine
AU - Kaplan, Warren
AU - Letai, Anthony
AU - Bourquin, Jean Pierre
AU - Houghton, Peter J.
AU - Smith, Malcolm A.
AU - Lock, Richard B.
PY - 2014/9/1
Y1 - 2014/9/1
N2 - 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.
AB - 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.
KW - Aniline Compounds/administration & dosage
KW - Apoptosis/drug effects
KW - Child
KW - Gene Expression Regulation, Neoplastic/drug effects
KW - Humans
KW - Myeloid Cell Leukemia Sequence 1 Protein/biosynthesis
KW - Neoplasm Proteins/biosynthesis
KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
KW - Proto-Oncogene Proteins c-bcl-2/genetics
KW - RNA, Messenger/biosynthesis
KW - Sulfonamides/administration & dosage
KW - Xenograft Model Antitumor Assays
UR - http://www.scopus.com/inward/record.url?scp=84919686238&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-14-0259
DO - 10.1158/1078-0432.CCR-14-0259
M3 - Article
C2 - 25013123
SN - 1078-0432
VL - 20
SP - 4520
EP - 4531
JO - Clinical Cancer Reserach
JF - Clinical Cancer Reserach
IS - 17
ER -
