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Review
. 2010 May;19(5):689-98.
doi: 10.1517/13543781003801076.

Suppression of farnesyltransferase activity in acute myeloid leukemia and myelodysplastic syndrome: current understanding and recommended use of tipifarnib

Pearlie K Epling-Burnette  1 , Thomas P Loughran Jr
Affiliations
Review

Suppression of farnesyltransferase activity in acute myeloid leukemia and myelodysplastic syndrome: current understanding and recommended use of tipifarnib

Pearlie K Epling-Burnette et al. Expert Opin Investig Drugs. 2010 May.

Abstract

Importance of the field: Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) incidence in the United States increases with age. Given the progressive ageing of the general population, incidence of these diseases is likely to continue to rise in the future. There is an acute need for therapeutic developments because of the poor prognosis of these diseases. Since the knowledge of molecular genetics in AML and MDS has expanded recently, targeted therapeutics should offer an exciting new frontier for advancement. Of all the targeted inhibitors developed, tipifarnib represents one of the few compounds with some activity as a single agent.

Areas covered in this review: Described in this review are the molecular targets of tipifarnib, safety and tolerability of the drug, chemistry, and clinical efficacy in AML.

What the reader will gain: The reader will gain a thorough understanding of tipifarnib as it relates to the current and future use of the drug in AML.

Take home message: The future of tipifarnib, along with other molecularly-targeted drugs, lies in achieving a better understanding of leukemia biology and harnessing the activity of this agent using predictive biomarkers for improved patient selection.

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Figures

Figure 1
Figure 1. Summary of Ras signaling pathway
RAS is activated by receptor tyrosine kinase (RTK) activation with several ligands that invoke these intermediates. Activation of the receptor leads to the activation of Ras nucleotide exchange factors such as GRB-2 and SOS that mediate the exchange of GDP for GTP and the recruitment of Raf and the activation of downstream factors such as Rac, Rho that mediate changes in the cytoskeleton, MEK and MAPK that mediate proliferation and PI3K and AKT that are necessary for survival. Other factors that mediate transcription such as the Janus Activating Kinase (Jak) lead to the Signal Transducer and Activator of Transcription (STAT) phosphorylation and transcription. This pathway has also been linked to tipifarnib response but the mechanism is unknown.
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