ALVOCIDIB SYNERGIZES WITH VENETOCLAX IN PRECLINICAL MODELS OF MULTIPLE MYELOMA
Author(s): ,
Hillary Haws
Affiliations:
Discovery Biology,Tolero Pharmaceuticals, Inc.,LEHI,United States
,
Mark Livingston
Affiliations:
Discovery Biology,Tolero Pharmaceuticals, Inc.,LEHI,United States
,
Wontak Kim
Affiliations:
Discovery Biology,Tolero Pharmaceuticals, Inc.,LEHI,United States
,
Ryan Mangelson
Affiliations:
Discovery Biology,Tolero Pharmaceuticals, Inc.,LEHI,United States
,
Peter Peterson
Affiliations:
Discovery Biology,Tolero Pharmaceuticals, Inc.,LEHI,United States
,
Clifford Whatcott
Affiliations:
Discovery Biology,Tolero Pharmaceuticals, Inc.,LEHI,United States
,
Adam Siddiqui-Jain
Affiliations:
Discovery Biology,Tolero Pharmaceuticals, Inc.,LEHI,United States
,
Steven Weitman
Affiliations:
Discovery Biology,Tolero Pharmaceuticals, Inc.,LEHI,United States
,
David Bearss
Affiliations:
Discovery Biology,Tolero Pharmaceuticals, Inc.,LEHI,United States
Steven Warner
Affiliations:
Discovery Biology,Tolero Pharmaceuticals, Inc.,LEHI,United States
(Abstract release date: May 18, 2017) EHA Learning Center. Warner S. May 18, 2017; 180980
Dr. Steven Warner
Dr. Steven Warner

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Abstract: E1204

Type: Eposter Presentation

Background
With over 30,000 new cases expected in 2016 (US), new treatments are desperately needed for the treatment of multiple myeloma (MM). Major developments in the treatment of MM have included introduction of agents such as lenalidomide, thalidomide, or bortezomib. Bortezomib, an inhibitor of the proteasome, reduces the degradation of many proteins, including the pro-apoptotic protein NOXA. However, high levels of MCL-1 and/or low basal levels of NOXA have been implicated in bortezomib resistance and negative patient outcomes. The BCL-2-specific BH3 mimetic, venetoclax (ABT-199), is also being explored in multiple hematologic malignancies, including multiple myeloma. However, intrinsic resistance to venetoclax treatment observed in MM patient samples has been attributed to a low BCL-2-to-MCL-1 gene expression ratio, suggesting a central role for MCL-1 in cell survival in this context as well. NOXA functions to sequester the anti-apoptotic BCL-2 family member, MCL-1. Increased MCL-1 expression is a known resistance mechanism to venetoclax treatment in a variety of cell types including chronic lymphocytic leukemia and lymphomas. Considering the central role of MCL-1 to treatment efficacy in MM, we investigated the ability of an MCL-1-lowering agent, namely the CDK9 inhibitor alvocidib, to potentiate the activity of venetoclax in MM. Alvocidib suppresses MCL-1 expression via CDK9-mediated regulation of RNA polymerase II. Alvocidib has demonstrated robust improvements in the clinical response rates of high-risk, newly diagnosed acute myeloid leukemia (AML) patients as part of the time-sequential ACM regimen (alvocidib + cytarabine + mitoxantrone).

Aims
We hypothesize that alvocidib would potentiate the activity of venetoclax in MM through an MCL-1-dependent mechanism.

Methods
CellTiter-Glo and Caspase-Glo were used for cell viability and apoptosis assays interrogating alvocidib and venetoclax in cell lines. We performed RT-PCR to measure mRNA levels of MCL-1 and other genes following treatment. Protein levels were interrogated using standard immunoblotting techniques. To determine the efficacy of an alvocidib/venetoclax combination on tumor growth in vivo, we performed a mouse study in the OPM-2 xenograft model.

Results
In this report, we demonstrate that alvocidib inhibited the protein expression of MCL-1 in MM cells in a time-dependent fashion, up to 96 hours. In cell viability assays, the addition of up to 100 nM venetoclax resulted in a 2.8-fold reduction in the IC50 of alvocidib in the cultured OPM-2 cell line. Conversely, the potentiation of venetoclax activity with the addition of alvocidib resulted in a more than 500-fold decrease in IC50 in the relatively venetoclax-resistant OPM-2 cells. Additional studies are currently underway to investigate the efficacy of alvocidib and venetoclax in the context of bortezomib resistance where low NOXA may contribute to enhanced cell survival via MCL-1.

Conclusion
Taken together, our data suggest that the combination of alvocidib with venetoclax may constitute a novel therapeutic regimen in the treatment of MM. Further, it suggests that CDK9-mediated targeting of MCL-1 may offer a clinical route to addressing intrinsic resistance in MM patients.

Session topic: 13. Myeloma and other monoclonal gammopathies - Biology

Keyword(s): Multiple Myeloma, Mcl-1, BCL2

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