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Research Articles: Therapeutics, Targets, and Development

Antitumor activity and molecular effects of the novel heat shock protein 90 inhibitor, IPI-504, in pancreatic cancer

¹ The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, ² McKusick-Nathans Institute of Genetic Medicine and Departments of Biological Chemistry and ³ Pathology and Oncology, Johns Hopkins University, Baltimore, Maryland; ⁴ Laboratorio de Dianas Terapéuticas, Centro Integral Oncológico Clara Campal, Hospital Madrid Norte Sanchinarro, Madrid, Spain; ⁵ Infinity Pharmaceuticals, Inc., Cambridge, Massachusetts; and ⁶ Institute of Bioinformatics, International Technology Park, Bangalore, India

Requests for reprints: Manuel Hidalgo, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans Street, Room 1M89, Baltimore, MD 21230. Phone: 410-502-3850; Fax: 410-614-9006. E-mail: mhidalg1{at}jhmi.edu

Abstract

Targeting Hsp90 is an attractive strategy for anticancer therapy because the diversity and relevance of biological processes are regulated by these proteins in most cancers. However, the role and mode of action of Hsp90 inhibitors in pancreatic cancer has not been studied. This study aimed to assess the antitumor activity of the Hsp90 inhibitor, IPI-504, in pancreatic cancer and to determine the biological effects of the agent. In vitro, we show that pharmacologic inhibition of Hsp90 by IPI-504 exerts antiproliferative effects in a panel of pancreatic cancer cells in a dose- and time-dependent manner. In pancreatic cancer xenografts obtained directly from patients with pancreas cancer, the agent resulted in a marked suppression of tumor growth. Although known Hsp90 client proteins were significantly modulated in IPI-504-treated cell line, no consistent alteration of these proteins was observed in vivo other than induction of Hsp70 expression in the treated xenografted tumors. Using a proteomic profiling analysis with isotope tags for relative and absolute quantitation labeling technique, we have identified 20 down-regulated proteins and 42 up-regulated proteins on IPI-504 treatment.tumor growth Identical changes were observed in the expression of the genes coding for these proteins in a subset of proteins including HSPA1B, LGALS3, CALM1, FAM84B, FDPS, GOLPH2, HBA1, HIST1H1C, HLA-B, and MARCKS. The majority of these proteins belong to the functional class of intracellular signal transduction, immune response, cell growth and maintenance, transport, and metabolism. In summary, we show that IPI-504 has potent antitumor activity in pancreatic cancer and identify potential pharmacologic targets using a proteomics and gene expression profiling. [Mol Cancer Ther 2008;7(10):3275–84]

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⁷ http://www.broad.mit.edu/gsea/

⁸ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

⁹ hprd.org

Received 5/29/08; revised 7/16/08; accepted 8/ 6/08.