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

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. Overall design: To gain insights into the molecular mechanisms underlying the anti-leukemic activity of ADV alone and in combination with VEN, we performed RNA-Seq on AML CD34+ blasts from R/R AML patients (n=6) treated with vehicle, ADV (5 μΜ), VEN (100 nΜ), or ADV+VEN for 24 hours. *************************************************************** due to patient privacy concern ***************************************************************

急性髓系白血病（acute myeloid leukemia, AML）患者的整体预后仍不容乐观，亟需开发更为有效的治疗策略。阿德福韦酯（adefovir dipivoxil, ADV）是核苷酸类似物阿德福韦的口服前体药物，可抑制病毒DNA聚合酶，是美国食品药品监督管理局（Food and Drug Administration, FDA）批准用于治疗乙型肝炎病毒感染的药物。近期已有研究报道了1例急性早幼粒细胞白血病患者应用ADV后展现出抗白血病活性的初步证据。本文报告了ADV单药及与venetoclax（VEN，一种口服FDA批准的BCL-2抑制剂）联合使用时的抗白血病活性，用于AML的治疗。
我们观察到，经ADV处理后，AML细胞系与CD34+原始细胞的凋亡水平显著升高、细胞增殖受到抑制，而健康供者的CD34+细胞则未出现此类变化。ADV与VEN联合应用具有协同抗白血病活性，可显著降低白血病干细胞（leukemia stem cell, LSC）负荷，并延长AML小鼠（即MllPTD/WT/Flt3ITD/ITD模型）及患者来源异种移植（patient derived xenograft, PDX）模型的生存期，其潜在机制可能为干扰白血病原始细胞的能量代谢并降低其凋亡阈值。
本研究结果为将这一“全口服”治疗方案转化为AML患者的临床治疗方案提供了理论依据，尤其适用于需要低强度治疗的患者。整体实验设计：为深入探究ADV单药及与VEN联合使用时抗白血病活性的分子机制，我们对复发性/难治性（relapsed/refractory, R/R）AML患者的AML CD34+原始细胞（n=6）开展了RNA-Seq测序，这些细胞分别经溶剂对照、ADV（5 μΜ）、VEN（100 nM）或ADV联合VEN处理24小时。
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