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Published on: July 20, 2016
AMG-176, an Mcl-1 Antagonist, Shows Preclinical Efficacy in Chronic Lymphocytic Leukemia
Xue Yi1,2, Aloke Sarkar1, Gorkem Kismali1,3
1Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Purpose:
Survival of CLL cells due to the presence of Bcl-2 and Mcl-1 has been established. Direct inhibition of Bcl-2 by venetoclax and indirect targeting of Mcl-1 with transcription inhibitors have been successful approaches for CLL. AMG-176 is a selective and direct antagonist of Mcl-1, which has shown efficacy in several hematologic malignancies; however, its effect on CLL is elusive. We evaluated biological and molecular effects of AMG-176 in primary CLL cells.
Experimental Design:
Using samples from patients (n = 74) with CLL, we tested effects of AMG-176 on CLL and normal hematopoietic cell death and compared importance of CLL prognostic factors on this biological activity. We evaluated CLL cell apoptosis in the presence of stromal cells and identified cell death pathway including stabilization of Mcl-1 protein. Finally, we tested a couplet of AMG-176 and venetoclax in CLL lymphocytes.
Results:
AMG-176 incubations resulted in time- and dose-dependent CLL cell death. At 100 and 300 nmol/L, there was 30% and 45% cell death at 24 hours. These concentrations did not result in significant cell death in normal hematopoietic cells. Presence of stroma did not affect AMG-176-induced CLL cell death. IGHV unmutated status, high β2M and Mcl-1 protein levels resulted in slightly lower cell death. Mcl-1, but not Bcl-2 protein levels, in CLL cells increased with AMG-176. Low concentrations of venetoclax (1-30 nmol/L) were additive or synergistic with AMG-176.
Conclusions:
AMG-176 is active in inducing CLL cell death while sparing normal blood cells. Combination with low-dose venetoclax was additive or synergistic.
Insights
AMG-176 effectively induces cell death in chronic lymphocytic leukemia (CLL) cells while sparing normal blood cells. Combining AMG-176 with venetoclax shows additive or synergistic effects, offering a promising new therapeutic strategy for CLL.
Area of Science:
- Oncology
- Hematology
- Molecular Biology
Background:
- Chronic lymphocytic leukemia (CLL) cell survival is mediated by anti-apoptotic proteins Bcl-2 and Mcl-1.
- Venetoclax directly inhibits Bcl-2, and transcription inhibitors indirectly target Mcl-1 in CLL treatment.
- AMG-176 is a novel, selective Mcl-1 antagonist with demonstrated efficacy in other hematologic malignancies.
Purpose of the Study:
- To investigate the biological and molecular effects of AMG-176 on primary CLL cells.
- To assess AMG-176's efficacy in inducing CLL cell death and its impact on normal hematopoietic cells.
- To evaluate the potential of combining AMG-176 with venetoclax for CLL treatment.
Main Methods:
- Primary CLL cells (n=74) and normal hematopoietic cells were treated with AMG-176.
- Cell death and apoptosis were measured in the presence and absence of stromal cells.
- Mcl-1 and Bcl-2 protein levels were assessed, along with the effect of prognostic factors.
- Combinations of AMG-176 and venetoclax were tested in CLL lymphocytes.
Main Results:
- AMG-176 induced time- and dose-dependent CLL cell death (30-45% at 100-300 nmol/L within 24 hours).
- Normal hematopoietic cells showed no significant cell death upon AMG-176 treatment.
- Mcl-1 protein levels increased with AMG-176, but Bcl-2 levels did not.
- Combinations of AMG-176 with low-dose venetoclax demonstrated additive or synergistic effects.
Conclusions:
- AMG-176 is a potent inducer of CLL cell death, selectively targeting malignant cells while sparing normal hematopoietic cells.
- The combination of AMG-176 with venetoclax presents a promising therapeutic strategy with additive or synergistic activity in CLL.
