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Identification of Molecular Predictors of Response in a Study of Tipifarnib Treatment in Relapsed and Refractory Acute Myelogenous Leukemia

Authors' Affiliations: ¹ Veridex, L.L.C. a Johnson & Johnson Company, San Diego, California; ² Service d'Hematologie Clinique, CHRU Hotel Dieu, Nantes, France; ³ H. Lee Moffitt Cancer Center and Research Institute, University of South Florida, Tampa, Florida; ⁴ Department of Hematology, Erasmus University Medical Center, Rotterdam, the Netherlands; ⁵ Adult Leukemia Program, Dana-Farber Cancer Institute, Boston, Massachusetts; and ⁶ Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Raritan, New Jersey

Requests for reprints: Mitch Raponi, Veridex, L.L.C., 3210 Merryfield Row, San Diego, CA 92121. Phone: 858-320-3319; Fax: 858-450-2093; E-mail: mraponi1{at}vrxus.jnj.com.

Purpose: Microarray technology was used to identify gene expression markers that predict response to the orally available farnesyltransferase inhibitor tipifarnib (Zarnestra, R115777) in acute myelogenous leukemia (AML).

Experimental Design: Gene expression profiles from 58 bone marrow samples from a cohort of relapsed and refractory AML patients were analyzed on the Affymetrix U133A gene chip that contains 22,000 genes.

Results: Supervised statistical analysis identified eight gene expression markers that could predict patient response to tipifarnib. The most robust gene was the lymphoid blast crisis oncogene (AKAP13), which predicted response with an overall accuracy of 63%. This gene provided a negative predictive value of 93% and a positive predictive value of 31% (increased from 18%). AKAP13 was overexpressed in patients who were resistant to tipifarnib. When overexpressed in the HL60 and THP1 cell lines, AKAP13 increased the resistance to tipifarnib by approximately 5- to 7-fold.

Conclusion: Diagnostic gene expression signatures may be used to select a group of AML patients that might respond to tipifarnib.

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