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Drug Repurposing for Gastrointestinal Stromal Tumor
Pessetto, Ziyan Y. Weir, Scott J. Sethi, Geetika Broward, Melinda Godwin, Andrew K.
Pessetto, Ziyan Y.
Weir, Scott J.
Sethi, Geetika
Broward, Melinda
Godwin, Andrew K.
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Abstract
Despite significant treatment advances over the past decade, metastatic gastrointestinal stromal tumor (GIST) remains largely incurable. Rare diseases, such as GIST, individually affect small groups of patients but collectively are estimated to affect 25–30 million people in the U.S. alone. Given the costs associated with the discovery, development and registration of new drugs, orphan diseases such as GIST are often not pursued by mainstream pharmaceutical companies. As a result, “drug repurposing” or “repositioning”, has emerged as an alternative to the traditional drug development process. In this study we screened 796 FDA-approved drugs and found that two of these compounds, auranofin and fludarabine phosphate, effectively and selectively inhibited the proliferation of GISTs including imatinib-resistant cells. One of the most notable drug hits, auranofin (Ridaura®), an oral, gold-containing agent approved by the FDA in 1985 for the treatment of rheumatoid arthritis (RA), was found to inhibit thioredoxin reductase (TrxR) activity and induce reactive oxygen species (ROS) production, leading to dramatic inhibition of GIST cell growth and viability. Importantly, the anti-cancer activity associated with auranofin was independent of IM resistant status, but was closely related to the endogenous and inducible levels of ROS, therefore is prior to IM response. Coupled with the fact auranofin has an established safety profile in patients, these findings suggest for the first time that auranofin may have clinical benefit for GIST patients, particularly in those suffering from imatinib-resistant and recurrent forms of this disease.
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Date
2013-07
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American Association for Cancer Research
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Broward_2013.pdf
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Keywords
Drug repurposing, Drug repositioning, Auranofin, Gastrointestinal stromal tumors treatment, Thioredoxin reductase activity
Citation
Pessetto, Z. Y., Weir, S. J., Sethi, G., Broward, M. A., & Godwin, A. K. (2013). Drug Repurposing for Gastrointestinal Stromal Tumor. Molecular Cancer Therapeutics, 12(7), 1299–1309. http://doi.org/10.1158/1535-7163.MCT-12-0968