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Synergistic Activity of Adefovir Dipivoxil and Venetoclax to Target the Bioenergetic Metabolism of Acute Myeloid Leukemia

ABSTRACT: The overall outcome of patients with acute myeloid leukemia (AML) remains poor and more effective strategies are urgently needed. Adefovir dipivoxil (ADV) is an oral prodrug of the nucleotide analogue adefovir that inhibits viral DNA polymerase and is a Food and Drug Administration (FDA)-approved drug for the treatment of hepatitis B virus. Preliminary evidence of the anti-leukemic activity of ADV was recently reported in a patient with acute promyelocytic leukemia. Herein we report on the anti-leukemic activity of ADV, alone and in combination with venetoclax (VEN), an oral FDA-approved BCL-2 inhibitor, for the treatment of AML. We observed a significant increase in apoptosis and reduction of cell growth both in AML cell lines and CD34+ blasts, but not in healthy donor CD34+ cells, after exposure to ADV. The combination of ADV and VEN had synergistic anti-leukemic activity and significantly reduced leukemia stem cell (LSC) burden and prolonged survival of AML murine (i.e., MllPTD/WT/Flt3ITD/ITD) and patient derived xenograft (PDX) models, likely by interfering with the bioenergetic metabolism of leukemic blasts and decreasing their apoptotic threshold. Our results provide a rationale for translating this “all oral” regimen to the clinic for treatment of AML patients, especially those requiring low intensity therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE261921 | GEO | 2024/03/24

REPOSITORIES: GEO

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8-Cl-Ado and 8-NH2-Ado Synergize with Venetoclax to Target the Methionine-MAT2A-SAM Axis in Acute Myeloid Leukemia

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caArray_golub-00392: Gefitinib (Iressa) induces myeloid differentiation of acute myeloid leukemia

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2015-05-16 | E-GEOD-68954 | biostudies-arrayexpress

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Project description:Acute myeloid leukemia (AML) is a clonal hematopoietic malignancy, characterized by expansion of immature leukemic blasts in the bone marrow. In AML, specific tyrosine kinases have been implicated in leukemogenesis, and are associated with poor treatment outcome. However, targeted therapy using kinase inhibitors (KIs) has had limited success, and may be improved by proper patient selection. We performed phosphotyrosine (pY) based, label-free phosphoproteomics to identify hyperphosphorylated, active kinases in two FLT3+ AML Pt samples.

2020-03-02 | PXD015639 | Pride

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2023-06-23 | PXD011399 | Pride

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2019-10-16 | PXD015520 | Pride

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