Drug repurposing identifies a synergistic combination therapy with imatinib mesylate for gastrointestinal stromal tumor.

Abstract

Gastrointestinal stromal tumor (GIST) is a rare and therefore often neglected disease. Introduction of the kinase inhibitor imatinib mesylate radically improved the clinical response of patients with GIST; however, its effects are often short-lived, with GISTs demonstrating a median time-to-progression of approximately two years. Although many investigational drugs, approved first for other cancers, have been subsequently evaluated for the management of GIST, few have greatly affected the overall survival of patients with advanced disease. We employed a novel, focused, drug-repurposing effort for GIST, including imatinib mesylate-resistant GIST, evaluating a large library of FDA-approved drugs regardless of current indication. As a result of the drug-repurposing screen, we identified eight FDA-approved drugs, including fludarabine phosphate (F-AMP), that showed synergy with and/or overcame resistance to imatinib mesylate. F-AMP induces DNA damage, Annexin V, and caspase-3/7 activities as the cytotoxic effects on GIST cells, including imatinib mesylate-resistant GIST cells. F-AMP and imatinib mesylate combination treatment showed greater inhibition of GIST cell proliferation when compared with imatinib mesylate and F-AMP alone. Successful in vivo experiments confirmed the combination of imatinib mesylate with F-AMP enhanced the antitumor effects compared with imatinib mesylate alone. Our results identified F-AMP as a promising, repurposed drug therapy for the treatment of GISTs, with potential to be administered in combination with imatinib mesylate or for treatment of imatinib mesylate-refractory tumors.

• Authors: Ziyan Y Pessetto, Yan Ma, Jeff J Hirst, Margaret von Mehren, Scott J Weir, Andrew K Godwin
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 13 Issue 10 Pg. 2276-87 (Oct 2014) ISSN: 1538-8514 [Electronic] United States
• PMID: 25122069 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Benzamides
• Piperazines
• Pyrimidines
• Vidarabine Phosphate
• fludarabine phosphate
• Imatinib Mesylate

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Benzamides (administration & dosage, pharmacology)
• Cell Proliferation (drug effects)
• Drug Repositioning
• Drug Synergism
• Female
• Gastrointestinal Stromal Tumors (drug therapy)
• High-Throughput Screening Assays
• Humans
• Imatinib Mesylate
• Mice
• Mice, Nude
• Piperazines (administration & dosage, pharmacology)
• Pyrimidines (administration & dosage, pharmacology)
• Vidarabine Phosphate (administration & dosage, analogs & derivatives, pharmacology)
• Xenograft Model Antitumor Assays