Cell and Molecular Determinants of in Vivo Efficacy of the Bh3 Mimetic Abt-263 against Pediatric Acute Lymphoblastic Leukemia Xenografts
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 comprised 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 co-culture 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 co-culture 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.
|ISBN||1078-0432 (Electronic) 1078-0432 (Linking)|
|Authors||Suryani, S. ; Carol, H. ; Ni Chonghaile, T. ; Frismantas, V. ; Sarmah, C. ; High, L. ; Bornhauser, B. ; Cowley, M. J. ; Szymanska, B. ; Evans, K. ; Boehm, I. ; Tonna, E. ; Jones, L. ; Moradi Manesh, D. ; Kurmasheva, R. T. ; Billups, C. A. ; Kaplan, W. ; Letai, A. ; Bourquin, J. P. ; Houghton, P. ; Smith, M. A. ; Lock, R. B.;|
|Publisher Name||CLINICAL CANCER RESEARCH|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/25013123|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/12448|