Abstract 5441: Preclinical assessment of the HDAC inhibitor JNJ-26481585: potent in vivo activity across a broad spectrum of human tumor xenografts

Abstract

Abstract JNJ-26481585 is a promising “second generation” oral pan-HDAC inhibitor. Recently, we have published data describing the identification and characterization of the molecule as a potent inhibitor of HDAC1 with a favorable pharmacodynamic profile. Subsequent analysis has shown that the compound has pan-HDAC inhibitory activity and demonstrates effective inhibition of tumor cell growth across a broad spectrum of solid and hematological tumor cell lines. Recent data has also shown that in vivo JNJ-26481585 alone, or in combination with bortezomib, is an effective agent in myeloma. Herein we describe the activity of JNJ-26481585 against a broad range of preclinical solid tumor xenograft models, at doses substantially below MTD and with different schedules of administration in order to address the clinical utility of this agent. Significant growth inhibition was achieved when dosing JNJ-26481585 at MTD with T/C in tumors of; A2780 ovarian tumor xenograft (3%), ras-mutant colon (HCT-116), (7%), MDA-MB-231 breast (38%), DU-145 prostate (11%) and lung H460, A549 and ras mutant NCI-H1373 (29%, 15% and 32% respectively). In the A2780 model, activity of JNJ-26481585 was superior to that of five other HDAC inhibitors tested. This class leading activity was observed at MTD and optimal route of administration of all compounds and importantly, we also observed significant activity of JNJ-26481585 at concentrations as low as 12.5% of MTD (T/C = 35%). Both class leading activity and significant tumor growth inhibition at concentrations substantially below MTD was also observed in A549, DU145 and HCT116 tumor xenografts. Furthermore, in HCT116, in line with taxotere in prostate models, JNJ-26481585 was shown to be more effective than the SOC, 5-FU. The HCT116 model was used further to address the potential of the compound for clinical utility by exploring alternative dosing schedules to that of QD IP dosing. 3 days on/4 days off, 1 week on/ 1 week off, Q2D and Q7D were all investigated alongside QD dosing and observed to inhibit tumor growth in all cases; Q7D was the only alternative schedule not to achieve efficacy equivalent to that with QD dosing. Finally, data indicating greater activity or equivalence with the SOC suggested that JNJ-26481585 could be used in those indications, thus potency was investigated in drug resistant patient material. In both taxol resistant NSCLC and doxorubicin resistant breast cancer cultures, JNJ-26481585 dramatically inhibited proliferation. We conclude that in preclinical models, JNJ-26481585 was effective at reducing the tumor size to the greatest extent of all HDAC agents studied. Potent antitumoral activity was also observed at doses substantially below MTD and from alternative dosing schedules, suggesting that this could be a promising agent for clinical development in such indications. 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 5441.