Abstract
The rational combination of bortezomib plus decitabine achieves clinical responses in AML.
Major finding: The rational combination of bortezomib plus decitabine achieves clinical responses in AML.
Mechanism: Bortezomib inhibits transcription of the gene encoding the receptor tyrosine kinase FLT3.
Impact: Bortezomib may sensitize patients with AML to decitabine treatment.
Treatment options for patients with acute myeloid leukemia (AML) who fail conventional chemotherapy remain limited, especially among elderly patients who may not be candidates for hematopoietic stem cell transplantation. Recent studies therefore have investigated the use of agents active in other hematologic diseases, including the proteasome inhibitor bortezomib and the DNA hypomethylating agent decitabine. Bortezomib has been shown to act as an indirect transcriptional inhibitor of AML target genes via upregulation of miR-29b and disruption of the transcription complex SP1/NFκB(p65) in vitro, and decitabine is clinically active in patients with chronic myelogenous leukemia as a single agent, with higher miR-29b levels associated with response. Based on these findings, Blum and colleagues investigated the safety, efficacy, and pharmacodynamics of bortezomib with decitabine in 19 poor-risk patients with AML. The combination was clinically active, achieving remission rates of 50% in previously untreated patients and 22% in patients with relapsed or refractory disease. Pharmacodynamic analysis revealed that all treated patients trended toward a higher expression of miR-29b and a lower expression of mRNA levels of FLT3, which encodes a receptor tyrosine protein kinase that is often mutated and overexpressed in AML. Using additional in vitro assays, the authors also determined that bortezomib targeted FLT3 expression through upregulation of miR-29b and disruption of transcriptional activation. Together, these clinical and molecular findings suggest that bortezomib may increase the efficacy of decitabine in patients with AML and that FLT3 levels may be used as a pharmacodynamic target of treatment response.
