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Abstract
Advances in the understanding of the genetic underpinnings of acute myeloid leukemia are rapidly being translated into novel treatment strategies. Genomic profiling has highlighted the importance of the epigenetic machinery for leukemogenesis by identifying recurrent somatic mutations involving chromatin-modifier proteins. These genetic alterations function as dynamic regulators of gene expression and involve DNA-methyltransferase 3A, methyltransferase DOT1L, enhancer of zeste homologue 2, isocitrate dehydrogenases 1 and 2 and bromodomain-containing proteins. New therapeutic targets are also emerging from further delineation of cell signaling networks in acute myeloid leukemia blasts mediated by PIM kinases, polo-like kinase 1, cell surface protein CD98 and nucleocytoplasmic shuttling receptors, among others. Early results of targeted therapies directed at these molecular mechanisms are discussed in this review and their potential to improve the outcomes of patients by allowing the use of more effective and less toxic treatments.
Financial & competing interests disclosure
JK Altman is participating in the Agios IDH and Epizyme DOT1L inhibitor clinical trials. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
Extensive genomic profiling of acute myeloid leukemia (AML) revealed recurrent alterations involving chromatin-modifier proteins highlighting the critical role of epigenetics in leukemogenesis.
Small-molecule inhibitor of DOT1L (EPZ-5676) currently undergoing Phase I trial in patients with advanced hematological malignancies carrying mixed lineage leukemia translocations represent the first rationally designed histone methyltransferase inhibitor in clinical trials.
Encouraging preliminary results with the bromodomain inhibitor in AML (OTX015) provide further support to the strategy of blocking protein–protein interactions to ultimately regulate epigenetic mechanisms.
The remarkable signal of efficacy and favorable toxicity profile of the first IDH2 mutant inhibitor (AG-221) in refractory AML provide impetus for future studies of modifiers of cancer metabolism.
Aminopeptidases regulate the degradation of peptides and control the supply of free amino acids. Promising results with the oral aminopeptidase inhibitor tosedostat in patients with advanced hematological malignancies provided support for ongoing trials investigating its efficacy in the frontline treatment of AML combined with chemotherapy.
Novel FMS-like tyrosine kinase 3 inhibitors with improved efficacy and specificity reinvigorated the interest in this class of agents. Crenolanib and quizartinib are being investigated in ongoing Phase III trials in combination with chemotherapy and as a single agent, respectively.
Efficacy of volasertib, inhibitor of Polo-like kinases, in refractory AML when administered in combination with low-dose cytarabine validated polo-like kinases as important therapeutic targets and fostered ongoing combination Phase III trials in elderly patients with AML.
Selinexor represents the first oral inhibitor of nucleocytoplasmic shuttling receptor CRM1 tested in Phase I trials for advanced AML with promising results.