VCU Institute of Molecular Medicine (VIMM) NEWS & VIEWS
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The VIMM, established in 2008 by Paul B. Fisher, M.Ph., Ph.D., the Founding Director, is comprised of outstanding scientists/clinicians from VCU School of Medicine focusing on important medical-related research in cancer, neurodegeneration and infectious diseases. The purpose of this NEWS & VIEWS is to highlight the exciting research being performed by the VIMM members.
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Co-targeting BCL-2 and PI3K Induces BAX-Dependent Mitochondrial Apoptosis in AML Cells
- Despite recent advances, acute myelogenous leukemia (AML) remains an incurable disorder in the majority of afflicted patients. Treatment options for patients with relapsed or refractory AML are particularly limited.
- AML cells exhibit dysregulation of members of the BCL-2 family of anti-apoptotic proteins, prompting the development of BH3-mimetics such as the selective BCL-2 antagonist, venetoclax (ABT-199).
- Initial studies suggest that venetoclax, when combined with other targeted agents, may have promising activity in this disease.
- Deregulation of the PI3 kinase pathway has also been implicated in AML, and has been linked to survival of primitive AML progenitors i.e., stem cells.
- A recent study by Dr. Steven Grant’s research group has shown that clinically relevant inhibitors of the PI3 kinase pathway synergistically enhance the anti-leukemic activity of venetoclax in AML cells, and that the mechanism underlying this phenomenon involves, at least in part, down-regulation of the anti-apoptotic protein MCL-1.
- This study provides a mechanistic foundation for a novel anti-leukemic strategy in which PI3 kinase inhibitors are rationally combined with BH3-mimetics such as venetoclax.
Acute myelogenous leukemia, particularly when it has relapsed following standard therapy, is one of the most intractable malignancies to treat. Recently, attention has focused on the pro-apoptotic BCL-2 antagonist venetoclax which has shown significant activity in AML when administered with low doses of a standard anti-leukemic agent, ara-C, leading to breakthrough status for the combination. These results have prompted efforts to combine venetoclax with targeted agents in an effort to achieve analogous success.
Previous work by the Grant laboratory demonstrated that inhibitors of the PI3 kinase pathway, a cascade previously implicated in the survival of AML stem cells, sharply potentiate the activity of other BH3-mimetics. The mechanism underlying this interaction involves inhibition of the pro-survival protein AKT, dephosphorylation and activation of the AKT target GSK3, and ubiquitination and degradation of the anti-apoptotic protein MCL-1, which confers resistance to the BH3-mimetic ABT-737, which targets BCL-2 and BCL-xL. Grant and colleagues discovered that clinically relevant PI3 kinase inhibitors also interact synergistically in AML cell lines and in primary AML cells, and, using genetic strategies, that a similar mechanism, i.e., MCL-1 down-regulation is involved. Moreover, using CRISPR-Cas technology, they found that BAX activation was essential for synergistic interactions. Notably, this approach was very effective against primitive AML populations enriched for leukemia stem cells. Significantly, the group found that the PI3 kinase inhibitor/venetoclax regimen is very active in animal models of AML, including patient-derived xenografts (PDX), but is minimally toxic, raising the possibility of a favorable therapeutic index. A manuscript describing these observations recently appeared in the June 1
st
edition of the journal Cancer Research*.
The implications of these findings are that in addition to combination of venetoclax with standard forms of therapy in AML, consideration should be given to the rational combination of this agent with targeted agents such as PI3 kinase. Plans to build upon this foundation are currently underway, as are efforts to extend this new strategy to other malignancies, e.g., non-Hodgkin’s lymphoma.
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Figure 1. Co-exposure of AML cells to venetoclax (Ven) and a PI3 kinase inhibitor (GDC) resulted in the striking translocation of Bax (green) to the mitochondria (red), reflected by increased yellow staining.
Figure 2. Combined treatment with venetoclax and the PI3 kinase inhibitor GDC significantly reduces marrow engraftment with human CD45+ cells compared to single drug treatment in two PDX AML mouse models. The means of different groups are statistically different for both patients AML1; P= 0.0013; AML2; P= 0.0051; one-way ANOVA.
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Support: This work was supported by awards from the National Cancer Institute/National Institutes of Health (CA205607, CA167708 S.G.), the National Center for Advancing Translational Science UH2TR001373 (S.G.), a Translational Research Award from the Leukemia and Lymphoma Society of America 6472-15 (S.G.), a Cancer Center Support Grant (NCI) to the Massey Cancer Center, and the Clinical and Translational Core Laboratory of the Massey Cancer Center.
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Publications:
Rahmani M
,
Aust MM
,
Hawkins E
,
Parker RE
,
Ross M
,
Kmieciak M
,
Reshko LB
,
Rizzo KA
,
Dumur CI
,
Ferreira-Gonzalez A
,
Grant S
.
Co-administration of the mTORC1/TORC2 inhibitor INK128 and the Bcl-2/Bcl-xL antagonist ABT-737 kills human myeloid leukemia cells through Mcl-1 down-regulation and AKT inactivation.
Haematologica.
2015 Dec;100(12):1553-63. PMCID:
PMC4666331
.
About the Investigators: Steven Grant, MD, is the Shirley and Sture Gordon Olsson Professor of Oncology, Professor of Medicine, Biochemistry, Pharmacology, and Human & Molecular Genetics, Associate Director of Translational Research and Co-Leader of the Experimental Therapeutics Program, Massey Cancer Center, and a Member of the VIMM. Lead author Mohamed Rahmani, PhD, is currently Associate Professor, College of Medicine and Sharjah Institute for Medical Research, University of Sharjah, Sharjah, United Arab Emirates.
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