Abstract 2606: Rational combinations with the HDAC inhibitor, JNJ-26481585, in prostate cancer
Authors: Hickson Ian , Marien Ann , Janssen Marc , Derks Maarten , King Peter , Verhulst Tinne , Janssens Boudewijn , Goehlmann Hinrich , Wyngaert Ilse Van Den , Axel Amy , Casneuf Tine , Bohets Hilde , Patrick Angibaud , Kumari Rajendra , Watson Sue , Arts Janine , Steve McClue , Page Martin 
Published: June 2012

Abstract
We have shown that the oral pan-HDAC inhibitor, JNJ-26481585, is a potent inhibitor of in vitro growth in a broad panel of solid and hematological tumor cell lines and western blot analysis confirmed modulation of HDAC1, 3 and 6 substrates (Arts et al, 2009). Inhibition of HDAC1 and 3 is associated with transcriptional suppression of target genes and regulation of tumor growth; modulation of HDAC6, impacting tubulin and Hsp90, results in depletion of oncogenic Hsp90 client proteins and potentiates tubulin acetylation with paclitaxel (Marcus et al, 2005; Valenzuela-Fernandez et al, 2008; Ai et al, 2009). We hypothesized that combinations between taxanes and JNJ-26481585 could result in enhanced tumor cell killing and describe our observations from such combinations in PC3-M prostate xenografts as a model of castrate resistant disease.
We have previously shown that JNJ-26481585 has significant activity in xenograft models of prostate cancer, including PC3-M. In comparative studies in mice, JNJ-26481585 has favorable tissue distribution, achieving higher levels of exposure than panobinostat and vorinostat in tissues including e.g. prostate (2-fold and 3-fold, respectively); a sustained PD response is also observed in lung and skin (suppression of Ki67 for 24h; elevation of AcH3). We further demonstrate that the levels of JNJ-26481585 observed in orthotopically implanted PC3-M tumors are superior to those of panobinostat or vorinostat (5-fold and 13-fold, respectively). Thus we selected this orthotopic model in order to define further how the distribution of JNJ-26481585 to target tissue contributes to efficacy. We found that the activity of taxotere alone was surpassed by that of JNJ-26481585 alone (tumor growth delay (TGD) of 5d for taxotere, and 15d for JNJ-26481585; vs vehicle) and significant TGD was observed from the combination of the agents (with 1mpk JNJ-26481585 = 20d; with 3mpk JNJ-26481585 = beyond study end).
The role of HDAC inhibition in the stability and regulation of the androgen receptor has recently been described as dependent on both HDAC1, 3 and 6 activities (Welsbie et al, 2009; Ai et al, 2009), which gives further support to our rationale for combining agents with JNJ-26481585. We hypothesized that JNJ-26481585 would be an efficacious agent when combined with abiraterone, an inhibitor of androgen synthesis. In LnCAP and VCaP prostate cancer cells, we showed by western blot analysis that exposure to JNJ-26481585 resulted in a dose dependent reduction in AR levels and profiling on Affymetrix microarrays also showed modulation of the expression of AR responsive genes e.g. KLKs and TMPRSS2. Consistent with a sustained PD response in tissues, we see continued reduction in AR levels and expression of AR dependent genes up to 24h after removal of compound. We continue to investigate the combination of JNJ-26481585 and abiraterone in vivo as our data provide strong support for the combination in prostate cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2606. doi:10.1158/1538-7445.AM2011-2606