Pharmacologic Targeting of miR29b with Bortezomib and Sorafenib to Improve Decitabine Sensitivity in Patients with Acute Myeloid Leukemia: Results from a Phase 1 Dose-Escalation Trial

Abstract

Background: Decitabine efficacy in acute myeloid leukemia (AML) may be enhanced by the pharmacologic upregulation of microRNA miR-29b, a regulator of DNA methyltransferase (DNMT) expression. Bortezomib and sorafenib have been shown preclinically to increase miR-29b levels, providing a biologically informed strategy to sensitize leukemic blasts to DNMT inhibition. Objectives: To evaluate the safety, tolerability, biological activity, and preliminary efficacy of combining bortezomib and sorafenib followed by decitabine in patients with newly diagnosed or relapsed/refractory AML. Methods: This phase I, dose-escalation study enrolled 15 patients (11 untreated, 4 relapsed/refractory) who received fixed-dose bortezomib and sorafenib across three dose levels prior to decitabine. Dose escalation was guided by dose-limiting toxicities (DLTs) and an increase in miR-29b expression. Results: The regimen was generally well tolerated with the most frequent grade ≥3 adverse events of hypertension and febrile neutropenia. At the highest dose level, a ≥2-fold increase in miR-29b expression was observed in two of the six evaluable patients. The overall response rate was 33.3%, with clinical responses observed in both newly diagnosed and relapsed/refractory patients. However, changes in miR-29b expression did not consistently correlate with clinical response. Conclusions: Sequential treatment with bortezomib and sorafenib followed by decitabine is feasible and demonstrates acceptable safety in AML. Although the biologic modulation of miR-29b was variable, this trial provides a proof of concept for pharmacodynamic-guided dose finding in epigenetic therapy combinations.