SCOR in Targeted Therapies for Infant Leukemias Project 2: Targeting Apoptosis in Leukemia in Infants
- Determine comprehensive gene and protein expression profiles of in vitro sensitivity
and resistance to obatoclax mesylate in multiple-lineage leukemia (MLL)-rearranged cell
lines and primary infant acute myeloid leukemia (AML) samples.
- Define optimum in vitro combinations of obatoclax mesylate targeting pro-survival BCL-2
family proteins with cytotoxic drugs in MLL-rearranged leukemia cell lines and primary
infant AML samples.
- Identify synergistic combinations based on a pharmacodynamic modeling and simulation
- Determine whether combinations of obatoclax mesylate targeting pro-survival BCL-2
family proteins with cytotoxic drugs improves survival in a xenograft model of
MLL-rearranged infant AML.
OUTLINE: This is a multicenter study.
Obatoclax mesylate activity is assessed via the MTT assay. A priori features of acute
myeloid leukemia (AML) blasts relating to the apoptosis and ATG cell death pathways and
their execution are characterized using microarray analysis and quantitative real-time
(Q-RT) PCR. Gene and protein expression is described and quantified using Q-RT PCR and
western blot analysis at specific time points after obatoclax mesylate exposure to identify
pharmacodynamic biomarkers of activity and characterize the cell death mechanism in
multiple-lineage leukemia (MLL)+ AML. The MTT assay is performed using obatoclax
mesylate-cytotoxic chemotherapy combinations to determine synergy focusing on common
cytotoxic drugs employed in AML treatment regimens.
Obatoclax mesylate efficacy is tested in a therapeutic NOG xenograft model of primary MLL+
Obatoclax mesylate activity
Carolyn A. Felix, MD
Children's Hospital of Philadelphia
United States: Federal Government