Initial testing of the histone deacetylase inhibitor Vorinostat by the Pediatric Preclinical Testing Program

C226 Background: Vorinostat is a small molecule inhibitor of histone deacetylase (HDAC), which like other HDAC inhibitors induces hyperacetylation of a number of proteins, resulting in a multitude of downstream effects. Increased levels of acetylated histones are associated with activation of expression of selected genes as well as with impaired mitotic progression. HDAC inhibitors also induce increased acetylation of non-histone proteins, including numerous transcription factors, Hsp90, Ku70, and α-tubulin. Vorinostat has been approved by the U.S. Food and Drug Administration for the treatment of cutaneous manifestations in patients with CTCL who have progressive, persistent or recurrent disease on or following two systemic therapies. Methods: The PPTP includes a molecularly characterized in vitro panel of cell lines (n=27) and in vivo panel of xenografts (n=61) representing most of the common types of childhood solid tumors and childhood ALL. Vorinostat in vitro testing used media containing 20% FCS and evaluated concentrations from 10 nM to 100 µM. Vorinostat was tested against the xenografts of the PPTP in vivo panels using intraperitoneal administration for six weeks (5-days on, 2-days off) at a dose of 125 mg/kg. Three measures of antitumor activity were used: 1) response criteria modeled after the clinical setting; 2) treated to control (T/C) tumor volume at day 21; and 3) a time to event (4-fold increase in tumor volume) measure based on the median EFS of treated and control lines (intermediate activity required EFS T/C > 2, and high activity additionally required a net reduction in median tumor volume at the end of the experiment). Results: Vorinostat was uniformly active against the PPTP in vitro panel with a median IC50 of 1.44 μM (range, 0.45 μM to 8.5 μM). Toxicity rates for treated and control animals were 12.7% and 1.7%, respectively, with 7 of 43 xenografts excluded from analysis for excessive toxicity. Vorinostat induced significant differences in EFS distribution compared to controls in 16 of 30 evaluable solid tumor xenografts, but in none of 6 evaluable acute lymphoblastic leukemia (ALL) xenografts. Although there were significant differences in EFS distribution in many of the PPTP solid tumor xenografts, no xenograft met the criteria for intermediate activity (EFS T/C > 2) for the time to event activity measure. No objective responses were observed in any of the solid tumor in vivo panels or in the ALL panel. The best response observed was PD2 (progressive disease with growth delay), which was noted in 9 of 30 evaluable solid tumor xenografts. Conclusions: Vorinostat has little activity as a single agent against the xenografts of the PPTP’s in vivo panel. These results do not exclude potential activity for vorinostat against a biological subtype of a pediatric cancer that is not represented within the PPTP panel. Given the limited in vivo activity observed for vorinostat, further preclinical work will focus on identifying vorinostat combinations with increased potential for having a favorable therapeutic index when translated into the pediatric clinical setting. Combinations of vorinostat with agents that modify transcriptional activity (e.g., retinoids and demethylating agents) are of particular interest for evaluation in pediatric preclinical models. (Supported by NCI NO1CM42216)