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Spotlight on Molecular Profiling

Asparagine synthetase as a causal, predictive biomarker for L-asparaginase activity in ovarian cancer cells

¹ Genomics and Bioinformatics Group, Laboratory of Molecular Pharmacology, ² Antibody and Protein Purification Unit, and ³ Gene Silencing Section, Office of Science and Technology Partnerships, Office of the Director, Center for Cancer Research, National Cancer Institute, NIH; ⁴ Special Diagnostics Section and ⁵ Molecular Signaling Section, Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, Maryland; ⁶ Cancer Research Institute, University of California San Francisco, San Francisco, California; ⁷ Enzon Pharmaceuticals, Inc., Piscataway, New Jersey; and ⁸ Translational Genomics Research Institute, Phoenix, Arizona

Requests for reprints: John N. Weinstein, Genomics and Bioinformatics Group, Room 5056B, 37 Convent Drive, Bethesda, MD 20892. Phone: 301-496-9571. E-mail: jw4i{at}nih.gov

Abstract

L-Asparaginase (L-ASP), a bacterial enzyme used since the 1970s to treat acute lymphoblastic leukemia, selectively starves cells that cannot synthesize sufficient asparagine for their own needs. Molecular profiling of the NCI-60 cancer cell lines using five different microarray platforms showed strong negative correlations of asparagine synthetase (ASNS) expression and DNA copy number with sensitivity to L-ASP in the leukemia and ovarian cancer cell subsets. To assess whether the ovarian relationship is causal, we used RNA interference to silence ASNS in three ovarian lines and observed 4- to 5-fold potentiation of sensitivity to L-ASP with two of the lines. For OVCAR-8, the line that expresses the least ASNS, the potentiation was >500-fold. Significantly, that potentiation was >700-fold in the multidrug-resistant derivative OVCAR-8/ADR, showing that the causal relationship between ASNS expression and L-ASP activity survives development of classical multidrug resistance. Tissue microarrays confirmed low ASNS expression in a subset of clinical ovarian cancers as well as other tumor types. Overall, this pharmacogenomic/pharmacoproteomic study suggests the use of L-ASP for treatment of a subset of ovarian cancers (and perhaps other tumor types), with ASNS as a biomarker for patient selection. [Mol Cancer Ther 2006;5(11):2613–23]

Grant support: The Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research; Pharmacology Research Associate Fellowship from National Institute of General Medical Sciences, NIH (P.L. Lorenzi); and program project grant CA 109552 from the Department of Health and Human Services (D.D. Von Hoff).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Competing interests statement: I.D. Horak is employed by Enzon Pharmaceuticals, Inc., which has an interest in pegylated L-ASP.

⁹ http://discover.nci.nih.gov; Shankavaram et al., Mol Cancer Ther, submitted.

¹⁰ http://www.genelogic.com/docs/pdfs/dataGenProductSheet.pdf.

¹¹ Gunsior et al., in preparation.

¹² Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 7/31/06; revised 10/ 4/06; accepted 10/ 5/06.

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