Evaluation of the Antitumor Efficacy, Pharmacokinetics, and Pharmacodynamics of the Histone Deacetylase Inhibitor Depsipeptide in Childhood Cancer Models In vivo

Abstract

Purpose: Histone acetyltransferases and histone deacetylases (HDAC) control the acetylation state of histones and other proteins regulating transcription and protein function. Several structurally diverse HDAC inhibitors have been developed as cancer therapeutic agents and in vitro have been shown to cause differentiation, cell cycle arrest, or apoptosis. Here, we have evaluated depsipeptide, a natural tetrapeptide HDAC inhibitor, against a panel of pediatric solid tumor models in vivo and evaluated pharmacokinetic and pharmacodynamic variables with tumor sensitivity. Experimental Design: Depsipeptide was administered at the maximum tolerated dose (4.4 mg/kg administered every 7 days  3 i.v. repeated q21d for a total of two cycles) to scid mice bearing 39 independently derived childhood tumors (9 brain tumors,11kidney cancers, 9 rhabdomyosarcomas, 3 neuroblastomas, and 7 osteosarcomas). Pharmacokinetic variables were determined, as were changes in histone and p53 acetylation, induction of p53 and p53 genotype, and alterations in Akt phosphorylation. Results: Of 39 tumors evaluated, three showed objective tumor regressions [two brain tumors (primitive neuroectodermal tumor and atypical teratoid malignant rhabdoid tumor) and oneWilms' tumor]. Depsipeptide inhibited growth of many tumor lines but achieved stable disease (<25% increase in volume during treatment cycle 1) in only two tumor models (anaplastic astrocytoma, two rhabdomyosarcomas, and a Wilms' tumor). Pharmacokinetic analysis showed that the population estimated AUC 0-24 was 1,123 ng h/mL, similar to the exposure following 13 mg/m 2 in ongoing phase I trials. Pharmacodynamic changes in histone acetylation (H2A, H2B, H3, and H4) in three depsipeptide-sensitive and three intrinsically resistant tumors followed a similar pattern; maximal increases in histone acetylation occurred at 8 hours and were elevated for up to 96 hours. In two sensitive tumor lines, IRS56 and BT27 (both wild-type p53) p53 increased in treated tumors being maximal at 8 hours and associated with induction of p21 cip1 , whereas p53 was stable in tumors with mutant p53. Sensitivity to depsipeptide did not correlate with p53 genotype, p53 acetylation, cleaved poly(ADP-ribose) polymerase, or phosphorylation of Akt (Ser 473 ). Conclusions: Our results show that depsipeptide inhibits its target in vivo causing increased histone acetylation; however, this does not correlate with drug sensitivity.The relatively low objective response rate [3 of 39 (8%) tumor lines showing greater than or equal to partial response and 4 (10%) stable disease] administered at dose levels that give clinically relevant drug exposures suggests that as a single agent depsipeptide may have limited clinical utility against pediatric solid tumors in a first-line setting.

Inhibition of histone deacetylase on ventricular remodeling in infarcted rats

“…The development of cardiac hypertrophy after infarction is a multigenic, integrative response involving signal integration of multiple pathways. HDAC inhibitors have shown efficacy as anticancer agents in humans and animal models (12,28). The cardiac effects of these agents are of interest, given the increasing likelihood of more widespread clinical use for noncardiac indications.…”

Tumor Models for Efficacy Determination

“…Th e development of human tumor xenograft models was a big step in moving toward more clinically relevant tumor models (35)(36)(37)(38)(39)(40). Th e advantages of using human tumor xenografts are that the malignant cells are human; many of these models are quite reproducible; there are a wide variety of tumor lines available; many of these lines have a long history and therefore a strong baseline of drug response data; the hosts are readily available; and statistically valid numbers of mice can be used in studies.…”

Low-Dose Histone Deacetylase Inhibitor Treatment Leads to Tumor Growth Arrest and Multi-Lineage Differentiation of Malignant Rhabdoid Tumors

“…Several studies now suggest that histone acetylation events are a key element of SMARCB1 function and MRT pathogenesis, leading to the study of histone de-acetylase inhibitors as potential therapy for MRT (8,(20)(21)(22)(23)(24). However, these studies have focused on HDACi as "cytotoxics" rather than differentiating agents.…”