Abstract 5443: Rational combinations with the HDAC inhibitor JNJ-26481585: Prostate cancer and taxane therapy
Authors: Hickson Ian , King Peter , Marien Ann , Vreys Veronique , Janssen Marc , Verhulst Tinne , Janssens Boudewijn , Angibaud Patrick , Kumari Rajendra , Watson Sue , Page Martin , Arts Janine 
Published: February 2011

We have recently reported the identification and characterization of JNJ-26481585, as a “second generation” oral pan-HDAC inhibitor. The compound has shown potent in vitro activity against solid and hematological tumor cell lines and significant induction of apoptosis was observed, consistent with the potency of JNJ-26481585 for Class I HDACs. In dose response to JNJ-26481585, western blot analysis of A2780 cell extracts confirmed modulation of HDAC1-3 substrates and also HDAC6 substrates. Inhibition of HDAC6, the deacetylase for tubulin and Hsp90, results in depletion of oncogenic Hsp90 client proteins, decreased cell motility, and potentiation of therapeutics such as taxanes. We hypothesized that rational combinations with taxanes and JNJ-26481585 could result in enhanced tumor cell killing and describe our observations from the combination of JNJ-26481585 in PC3-M prostate tumors.

Combinations of JNJ-26481585 and taxanes were performed by co-administration or 24h separation of agents in A549, NCI-H460, NCI-H1373, NCI-H1703, NCI-H322 and NCI H-1650 lung cell lines; breast cell lines, MDA-MB-231, T47D, BT474 and MCF-7 cells; and prostate cell lines PC3M, DU-145, 22Rv1 and LnCap. We will present data on the outcome of these combinations, including additive and synergistic effects.

The in vitro data encouraged us to explore the effects of the compound in vivo and in prostate models where we already had excellent single agent activity for JNJ-26481585 in DU-145, PC-3 and the PC-3M orthotopic model (significant T/C values in each model and at doses substantially below MTD). In PC3-M xenograft models, the combination of 1.25, 5 or 10mpk JNJ-26481585 (Q2D) and taxotere (Q7D), was more effective than either agent alone and resulted in dose dependent tumor regression and substantial extension of time to relapse. We then selected the more challenging PC-3M orthotopic mouse model to further define the contribution to efficacy from the excellent tissue distribution of our agent. Comparing 5mpk taxotere (Q7D), with 1 or 3mpk of JNJ-26481585 (QD) or the combination of agents, the activity of taxotere alone was surpassed by either dose of HDAC inhibitor alone and substantial tumor growth delay was observed from the combination of 3mpk JNJ-26481585 and taxotere; activity greater than predicted from the in vitro experiments.

Finally, although HDAC6 inhibition could directly explain potentiation of taxotere by JNJ-26481585 in vitro, we believe the substantial effects in vivo may be due to the anti-angiogenic effect observed for our agent. We present also our data showing anti-angiogenic effects of JNJ-26481585 in PC3-M tumors, consistent with this hypothesis. Our data support the further use of more complex models, reflective of human disease in preclinical assessment and also support further exploration of this agent in rational combinations with SOC agents. JNJ-26481585 is currently in Phase I clinical trials.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5443.