# 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

## TL;DR

This study tested combining bortezomib and sorafenib with decitabine to treat AML, aiming to increase miR-29b levels and improve treatment response.

## Contribution

The study introduces a pharmacodynamic-guided approach to dose-finding in epigenetic therapy combinations for AML.

## Key findings

- The treatment was generally safe with a 33.3% overall response rate in AML patients.
- MiR-29b levels increased in some patients, but not consistently linked to treatment response.
- The approach demonstrates feasibility of using biological markers to guide drug dosing in AML.

## Abstract

Decitabine is a commonly used drug for acute myeloid leukemia (AML), an aggressive blood cancer, but it does not work equally well for all patients. Our study tested whether giving two other approved drugs, bortezomib and sorafenib, before decitabine could make the leukemia cells more sensitive to treatment. The goal was to raise the levels of a genetic regulator called microRNA-29b, which has been linked to better responses to decitabine. In this early-phase clinical trial, 15 patients with newly diagnosed or relapsed AML were treated with increasing doses of this drug combination to identify the dose that best increased microRNA-29b levels. The treatment was generally safe, and about one-third of patients showed improvement in their leukemia. However, increases in microRNA-29b were not consistently linked to treatment response. A key strength of this study is its use of a biological marker to guide drug dosing, an approach that may help improve future AML treatments.

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.