Combining p38MAPK Inhibitors with a Second Targeted Agent Enhances Blockade of Inflammatory Signaling-Mediated Survival in Acute Myeloid Leukemia Cells

Background: Various pro-inflammatory and stress-related stimuli activate p38 mitogen-activated protein kinase (p38MAPK), triggering cascades of cell proliferation, differentiation, and apoptosis signaling. We have previously found that inflammatory cytokines promote growth and survival in primary cells from acute myeloid leukemia (AML) patients. The downstream mediator of inflammatory pathways is p38MAPK, and blocking this regulator with kinase inhibitors abrogates inflammation signaling in AML cells.Methods: We used a functional ex vivo screening assay to identify small-molecule targeted inhibitors and inhibitor combinations demonstrating selective efficacy across broad categories of leukemia. Primary mononuclear cells isolated from leukemia patients (n=408) were plated in the presence of the p38MAPK inhibitor doramapimod or combinations of doramapimod with a second targeted agent that inhibits or effects a non-overlapping biological pathway. A 7-point concentration series was evaluated for both single agent inhibitors and combinations. Leukemia specimens from 408 unique patients were classified into 5 diagnosis subgroups including acute myeloid leukemia (AML; n=206), acute lymphoblastic leukemia (ALL; n=42), chronic lymphocytic leukemia (CLL; n=115), chronic myeloid leukemia (CML; n=16) and myeloproliferative neoplasms/myelodysplastic syndrome (MPN or MDS/MPN; n=29). IC50 and AUC values were derived from probit-based regression for each response curve. Mutational status for...
Source: Blood - Category: Hematology Authors: Tags: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Poster II Source Type: research

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Source: Diabetologia - Category: Endocrinology Source Type: research
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Source: Expert Opinion on Investigational Drugs - Category: Drugs & Pharmacology Tags: Expert Opin Investig Drugs Source Type: research
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Source: Expert Opinion on Investigational Drugs - Category: Drugs & Pharmacology Tags: Expert Opin Investig Drugs Source Type: research
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Source: Journal of Investigative Dermatology - Category: Dermatology Tags: Editor's Choice Source Type: research
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Source: Journal of Bone Oncology - Category: Cancer & Oncology Source Type: research
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Source: Journal of Cancer Research and Clinical Oncology - Category: Cancer & Oncology Source Type: research
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Source: Journal of Cancer Research and Clinical Oncology - Category: Cancer & Oncology Source Type: research
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Source: Journal of Cancer Research and Clinical Oncology - Category: Cancer & Oncology Source Type: research
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Source: Journal of Cancer Research and Clinical Oncology - Category: Cancer & Oncology Source Type: research
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