Cell and molecular determinants of in vivo efficacy of the BH3 mimetic ABT-263 against pediatric acute lymphoblastic leukemia xenografts

Santi Suryani, Hernan Carol, Triona N.i. Chonghaile, Viktoras Frismantas, Chintanu Sarmah, Laura High, Beat Bornhauser, Mark J. Cowley, Barbara Szymanska, Kathryn Evans, Ingrid Boehm, Elise Tonna, Luke Jones, Donya M.oradi Manesh, Raushan T. Kurmasheva, Catherine Billups, Warren Kaplan, Anthony Letai, Jean Pierre Bourquin, Peter J. HoughtonMalcolm A. Smith, Richard B. Lock

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4520-4531
Number of pages12
JournalClinical cancer research : an official journal of the American Association for Cancer Research
Volume20
Issue number17
DOIs
StatePublished - Sep 1 2014
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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