title: Cell and molecular determinants of in vivo efficacy of the BH3 mimetic ABT-263 against pediatric acute lymphoblastic leukemia xenografts.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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%).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: Santi
authors.initials: S
authors.lastname: Suryani
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: Hernan
authors.initials: H
authors.lastname: Carol
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Triona Ni
authors.initials: TN
authors.lastname: Chonghaile
authors.affiliation: Division of Pediatric Oncology, University Children's Hospital, Zurich, Switzerland.
authors.forename: Viktoras
authors.initials: V
authors.lastname: Frismantas
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: Chintanu
authors.initials: C
authors.lastname: Sarmah
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: Laura
authors.initials: L
authors.lastname: High
authors.affiliation: Division of Pediatric Oncology, University Children's Hospital, Zurich, Switzerland.
authors.forename: Beat
authors.initials: B
authors.lastname: Bornhauser
authors.affiliation: Peter Wills Bioinformatics Centre, Garvan Institute of Medical Research, Darlinghurst, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Cowley
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: Barbara
authors.initials: B
authors.lastname: Szymanska
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Evans
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Boehm
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: Elise
authors.initials: E
authors.lastname: Tonna
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: Luke
authors.initials: L
authors.lastname: Jones
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, Australia.
authors.forename: Donya Moradi
authors.initials: DM
authors.lastname: Manesh
authors.affiliation: Center for Childhood Cancer, Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Raushan T
authors.initials: RT
authors.lastname: Kurmasheva
authors.affiliation: Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, Tennessee.
authors.forename: Catherine
authors.initials: C
authors.lastname: Billups
authors.affiliation: Peter Wills Bioinformatics Centre, Garvan Institute of Medical Research, Darlinghurst, Australia.
authors.forename: Warren
authors.initials: W
authors.lastname: Kaplan
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Anthony
authors.initials: A
authors.lastname: Letai
authors.affiliation: Division of Pediatric Oncology, University Children's Hospital, Zurich, Switzerland.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bourquin
authors.affiliation: Center for Childhood Cancer, Nationwide Children's Hospital, Columbus, Ohio.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
authors.affiliation: Cancer Therapy Evaluation Program, NCI, Bethesda, Maryland.
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Smith
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, Sydney, Australia. rlock@ccia.unsw.edu.au.
authors.forename: Richard B
authors.initials: RB
authors.lastname: Lock
mesh_terms: D000814:Aniline Compounds / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D002648:Child; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000096:biosynthesis; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D013449:Sulfonamides / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000814:Aniline Compounds; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D013449:Sulfonamides; C528561:navitoclax