Journal
CANCER
Volume 119, Issue 2, Pages 293-303Publisher
WILEY-BLACKWELL
DOI: 10.1002/cncr.27743
Keywords
Connectivity Map; cholangiocarcinoma; NVP-AUY922; drug repurposing; heat-shock protein 90
Categories
Funding
- Taiwan Cancer Clinic Foundation
- Yen Tjing Ling Medical Foundation [101DHA0100657, 101DHA0100653, CMRPG390931, CMRPG3B0361]
- National Science Center [97-2314-B-182A-020-MY3, 100-2627-B-010-005-]
- National Health Research Institutes [EX101-10029BI]
- National Taiwan Normal University [100NTNU-D-06]
- Ministry of Economic Affairs [100-EC-17-A-17-S1-152]
- Ministry of Education, Aim for the Top University Plan (National Yang Ming University)
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BACKGROUND. Cholangiocarcinoma (CCA) is an aggressive tumor with a poor prognosis. There is no standard therapy for CCA, and novel drugs for treating refractory CCA need to be identified. METHODS. The authors hypothesized that, if a drug could reverse the gene expression signature of CCA, then it may inhibit the carcinogenesis of CCA and, hence, would be a potential therapeutic agent. Thus, the gene expression signatures from patients with CCA were queried using the bioinformatic method Connectivity Map, resulting in the enrichment of heat-shock protein 90 (HSP90) inhibitors with therapeutic potentials. RESULTS. Two HSP90 inhibitors, 17-AAG (tanespimycin) and the synthetic diarylisoxazole amide resorcinol NVP-AUY922, demonstrated potent antiproliferative activity in in vitro studies. In a thioacetamide-induced animal model, NVP-AUY922 also had antitumor activity and resulted in objective tumor regression. In addition, NVP-AUY922 reduced the expression of client oncoproteins involved in CCA oncogenesis and inhibited downstream proteins of both the phosphatidylinositol 3-kinase catalytic subunit a/v-akt murine thymoma viral oncogene homolog 1 protein kinase (PIK3/AKT) pathway and the v-Ki-ras2 Kirsten rat sarcoma viral oncogene/mitogen-activated protein kinase (KRAS/MAPK) pathway. CONCLUSIONS. Preclinical data from the current study suggest that NVP-AUY922 may be an effective treatment option for patients with CCA. Cancer 2013. (c) 2012 American Cancer Society.
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