Inhibition of Survivin with YM155 Induces Durable Tumor Response in Anaplastic Thyroid Cancer

Abstract

Purpose Anaplastic thyroid cancer (ATC) is a rare but lethal malignancy without any effective therapy. The aim of the present study was to use a high-throughput drug library screening to identify a novel therapeutic agent that targets dysregulated genes/pathways in ATC. Experimental Design We performed quantitative high-throughput screening (qHTS) in ATC cell lines using a compound library of 3,282 drugs. Dysregulated genes in ATC were analyzed using genome-wide expression analysis and immunohistochemistry in human ATC tissue samples and ATC cell lines. In vitro and in vivo studies were performed for determining drug activity, effectiveness of targeting, and the mechanism of action. Results qHTS identified 100 active compounds in three ATC cell lines. One of the most active agents was the first-in-class survivin inhibitor YM155. Genome-wide expression analysis and immunohistochemistry showed overexpression of survivin in human ATC tissue samples, and survivin was highly expressed in all ATC cell lines tested. YM155 significantly inhibited ATC cellular proliferation. Mechanistically, YM155 inhibited survivin expression in ATC cells. Furthermore, YM155 treatment reduced claspin expression, which was associated with S-phase arrest in ATC cells. In vivo, YM155 significantly inhibited growth and metastases and prolonged survival. Conclusions Our data show that YM155 is a promising anticancer agent for ATC and that its target, survivin, is overexpressed in ATC. Our findings support the use of YM155 in clinical trials as a therapeutic option in advanced and metastatic ATC.

Efficient inhibition of ovarian cancer by degradable nanoparticle-delivered survivin T34A gene

“…36 Mehta et al have proved that YM155, a small molecule, could specifically inhibit survivin gene expression by suppressing its promoter activity, which has been proved to inhibit esophageal squamous-cell carcinoma growth in mice. 37 In addition, dominant-negative mutant was another method of choice to suppress the antiapoptotic function of survivin. Previous studies have reported that dominant-negative mutant (threonine 34 to alanine) of survivin has been shown to attenuate the endogenous survivin expression through abolishing of cdc2-cyclin B1 complex-mediated phosphorylation.…”

YM155 inhibits topoisomerase function

“…So far preclinical data predict that YM155 would be useful in patients with breast, prostate, lung cancer and mantle cell lymphoma[35], in which topoisomerase poison have made important contributions to treatment. Interestingly, anaplastic thyroid cancer that expresses TOP2α five-fold higher than differentiated thyroid cancer (Personal data) was exquisitely sensitive to YM155 [36]. Uncertainty of the molecular target and lack of rationale combination in an unselected population were likely responsible for the failure of YM155 in recent clinical trials.…”

Exploiting AR-Regulated Drug Transport to Induce Sensitivity to the Survivin Inhibitor YM155

“…YM155 was originally developed to suppress the transcription of BIRC5(48). Subsequent studies measuring the efficacy of YM155 in over 100 human cancer cell lines and xenografts found YM155 to potently cause cell death across a broad spectrum of cancers with low systemic toxicity in xenografts(59–61). YM155 inhibits BIRC5 by perturbing transcription factor-DNA interactions of Sp-1(62), ILF3(63), p50(64), and NONO(65).…”