Emerging therapeutic targets for the treatment of human acute myeloid leukemia (part 1) – gene transcription, cell cycle regulation, metabolism and intercellular communication

Abstract

Human acute myeloid leukemia is a heterogeneous disease and the effect of therapeutic targeting of specific molecular mechanisms will probably vary between patient subsets. Cell cycle regulators are among the emerging targets (e.g., aurora and polo-like kinases, cyclin-dependent kinases). Inhibition of communication between acute myeloid leukemia and stromal cells is also considered; among the most promising of these strategies are inhibition of hedgehog-initiated, CXCR4–CXCL12 and Axl-Gas6 signaling. Finally, targeting of energy and protein metabolism is considered, the most promising strategy being inhibition of isocitrate dehydrogenase in patients with IDH mutations. Thus, several strategies are now considered, and a major common challenge for all of them is to clarify how they should be combined with each other or with conventional chemotherapy, and whether their use should be limited to certain subsets of patients.

Keywords:

• acute myeloid leukemia
• cell cycle
• clinical studies
• CXCL12
• hedgehog signaling
• isocitrate dehydrogenase
• mesenchymal stem cell

Financial & competing interests disclosure

The authors were all supported by the Norwegian Cancer Society, the Solveig and Ove Lundes Foundation and the Heels-Vest. 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.

Key issues

• Acute myeloid leukemia is a heterogeneous disease both with regard to genetic abnormalities and the phenotype of the leukemic cell (i.e., molecular mechanisms involved in leukemogenesis), and the most effective therapeutic targeting of molecular mechanisms that are driving the leukemogenesis will probably differ between patients.

• Inhibition of the JAK2-STAT3 pathway should be considered as a possible therapeutic strategy at least for certain acute myeloid leukemia patients, but additional biological studies are needed before clinical studies can be designed.

• Inhibition of cell cycle progression is tried through targeting of single targets (aurora kinase or polo-like kinase 1 inhibition) or through combined targeting (CDK2/CDK4 inhibitors, cell division cycle 25 inhibition).

• Other possible strategies are targeting of: communication between leukemic and stromal cells (hedgehog, Axl-Gas6, CXCR4–CXCL12 signaling) and energy metabolism (especially isocitrate dehydrogenase inhibition in patients with IDH mutations).

• Major future challenges are to clarify whether these strategies should be used as single-drug treatment or in combinations, and whether they should be used only for certain subsets of patients.

Notes