Initial testing (stage 1) of the histone deacetylase inhibitor, quisinostat (JNJ‐26481585), by the Pediatric Preclinical Testing Program. Issue 2 (4th September 2013)

• Record Type: Journal Article
• Authors: Carol, Hernan; Gorlick, Richard; Kolb, E. Anders; Morton, Christopher L.; Manesh, Donya Moradi; Keir, Stephen T.; Reynolds, C. Patrick; Kang, Min H.; Maris, John M.; Wozniak, Amy; Hickson, Ian; Lyalin, Dmitry; Kurmasheva, Raushan T.; Houghton, Peter J.; Smith, Malcolm A.; Lock, Richard
• Is Part Of: Pediatric blood & cancer. Volume 61:Issue 2(2014:Feb.)
• Page Start: 245
• Page End: 252
• Publication Date: 2013-09-04
• Subjects: Tumors in children -- Periodicals; Blood -- Diseases -- Periodicals; Cancer in children -- Periodicals; 618.92
• DOI: 10.1002/pbc.24724
• Languages: English
• ISSNs: 1545-5009

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <sec id="pbc24724-sec-0001" sec-type="section"> <title>Background</title> <p>Quisinostat (JNJ‐26481585) is a second‐generation pyrimidyl‐hydroxamic acid histone deacetylase (HDAC) inhibitor with high cellular potency towards Class I and II HDACs. Quisinostat was selected for clinical development as it showed prolonged pharmacodynamic effects <italic>in vivo</italic> and demonstrated improved single agent antitumoral efficacy compared to other analogs.</p> </sec> <sec id="pbc24724-sec-0002" sec-type="section"> <title>Procedures</title> <p>Quisinostat was tested against the PPTP <italic>in vitro</italic> panel at concentrations ranging from 1.0 nM to 10 μM and was tested against the PPTP <italic>in vivo</italic> panels at a dose of 5 mg/kg (solid tumors) or 2.5 mg/kg (ALL models) administered intraperitoneally daily × 21.</p> </sec> <sec id="pbc24724-sec-0003" sec-type="section"> <title>Results</title> <p> <italic>In vitro</italic> quisinostat demonstrated potent cytotoxic activity, with T/C% values approaching 0% for all of the cell lines at the highest concentration tested. The median relative IC<sub>50</sub> value for the PPTP cell lines was 2.2 nM (range <1–19 nM). quisinostat induced significant differences in EFS distribution compared to control in 21 of 33 (64%) of the evaluable solid tumor xenografts and in 4 of 8 (50%) of the evaluable ALL xenografts. An objective response was observed in 1 of 33 solid tumor xenografts while for the ALL panel, two xenografts achieved complete response (CR) or maintained CR, and a third ALL xenograft achieved stable disease.</p> </sec> <sec id="pbc24724-sec-0004" sec-type="section"> <title>Conclusions</title> <p>Quisinostat demonstrated broad activity <italic>in vitro</italic>, and retarded growth in the majority of solid tumor xenografts studied. The most consistent <italic>in vivo</italic> activity signals observed were for the glioblastoma xenografts and T‐cell ALL xenografts. Pediatr Blood Cancer 2014;61:245–252. © 2013 Wiley Periodicals, Inc.</p> </sec> </abstract>