ALVOCIDIB POTENTIATES THE ACTIVITY OF ABT-199 IN NONCLINICAL MODELS OF ACUTE MYELOID LEUKEMIA
Author(s): ,
Clifford Whatcott
Affiliations:
Tolero Pharmaceuticals, Inc.,Lehi,United States
,
James Bogenberger
Affiliations:
Mayo Clinic,Scottsdale,United States
,
Wontak Kim
Affiliations:
Tolero Pharmaceuticals, Inc.,Lehi,United States
,
Katherine Soh
Affiliations:
Tolero Pharmaceuticals, Inc.,Lehi,United States
,
Ye Sol Lee
Affiliations:
Tolero Pharmaceuticals, Inc.,Lehi,United States
,
Peter Peterson
Affiliations:
Tolero Pharmaceuticals, Inc.,Lehi,United States
,
Kyle Maughan
Affiliations:
Tolero Pharmaceuticals, Inc.,Lehi,United States
,
Adam Siddiqui-Jain
Affiliations:
Tolero Pharmaceuticals, Inc.,Lehi,United States
,
Steven Weitman
Affiliations:
Tolero Pharmaceuticals, Inc.,Lehi,United States
,
David Bearss
Affiliations:
Tolero Pharmaceuticals, Inc.,Lehi,United States
,
Steven Warner
Affiliations:
Tolero Pharmaceuticals, Inc.,Lehi,United States
Raoul Tibes
Affiliations:
Mayo Clinic,Scottsdale,United States
EHA Learning Center. Whatcott C. Jun 11, 2016; 133445
Dr. Clifford Whatcott
Dr. Clifford Whatcott
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Abstract: P557

Type: Poster Presentation

Presentation during EHA21: On Saturday, June 11, 2016 from 17:30 - 19:00

Location: Poster area (Hall H)

Background
The BCL-2 inhibitor ABT-199 (or venetoclax) has recently received FDA breakthrough therapy designation for use in combination with hypomethylating agents (HMAs) in patients with acute myeloid leukemia (AML). Early stage trials have demonstrated clinical response rates over 70% in combination with HMAs (azacitidine or decitabine) in previously untreated elderly patients with AML. Single-agent activity of ABT-199 was modest in AML, and resistance is developing in combination regimens. One proposed mechanism of resistance is compensatory up-regulation of other BCL-2 family proteins such as MCL-1, which plays a general role in resistance to BCL-2 inhibitors. The CDK9 inhibitor, alvocidib, as a component of a sequential regimen with chemotherapy, demonstrated a superior rate of complete remission in newly diagnosed intermediate and high-risk AML patients over standard induction chemotherapy in a randomized multi-center Phase 2 trial. We and others have demonstrated that alvocidib inhibition of CDK9 can mediate transcriptional repression of anti-apoptotic MCL-1. Further, we and others have shown that alvocidib can increase pro-apoptotic BIM (a pan BH3-only protein) in some cells. BIM is known to neutralize all anti-apoptotic BCL-2 family proteins such as MCL-1 and BCL-2, thus having a similar net effect on mitochondrial outer membrane permeabilization (MOMP)-induced apoptosis as MCL-1 down-regulation. Therefore, we hypothesize that alvocidib and ABT-199 synergize in the treatment of AML by shifting the balance/activity of pro- versus anti-apoptotic BCL-2 family members in favor of apoptosis induction.

Aims
These studies sought to investigate the nonclinical activity of the combination of alvocidib with ABT-199 in the context of (drug-resistant) AML.

Methods
CellTiter-Glo was used for all cell viability assays interrogating alvocidib and ABT-199 activity in cell lines, following manufacturer’s protocol. RT-PCR was used to measure mRNA expression of MCL-1 and other markers in response to drug treatment. Protein expression was assessed using standard western blotting techniques. To determine the efficacy of an alvocidib/ABT-199 combination on tumor growth in an in vivo model, multiple xenograft mouse models, and ex vivo studies with AML patient samples were performed.

Results
In this report, we demonstrate that alvocidib inhibits both mRNA and protein expression of MCL-1 in a time and concentration-dependent fashion in a majority of AML cell lines analyzed. Additionally, in a cell line for which alvocidib did not reduce MCL-1 protein levels (MOLM-13), we observe a potent, dose-dependent increase in BIM protein after 24 hours of alvocidib treatment. Concurrent treatment of alvocidib with ABT-199 in standard 96-hour assays resulted in potent, dose-dependent, synergistic reductions of cell viability in ABT-199-sensitive and resistant cells. ABT-199-sensitive lines, MV4-11 and MOLM-13, exhibited 5- to 10-fold reduction of ABT-199 EC50 values in the low nM range when combined with 80 nM alvocidib. Importantly, ABT-199-resistant lines, OCI-AML3 and THP-1, exhibited at least a 20-fold reduction of ABT-199 EC50 values from near 1 μM to 10-50 nM, when combined with 80 nM alvocidib. Xenografts models, as well as ex vivo drug synergy studies with AML patient samples, are currently under way to interrogate the efficacy of this combination.

Conclusion
Taken together, our data suggest that the combination of alvocidib with ABT-199 could be a novel therapeutic regimen in both ABT-199-sensitive and -resistant AML across a heterogeneous genomic background. Although reduction of MCL-1 by alvocidib may be associated with synergy in some cells, other mechanism(s) are operating as well. We conclude that a CDK9 inhibitor/ABT-199 combination may be a novel approach for the treatment of AML and warrants further pre-clinical and clinical validation. To this effect, animal models are underway, as are plans for clinical trials.

Session topic: Acute myeloid leukemia - Biology 3

Keyword(s): Apoptosis, BCL2, Mcl-1
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