Evaluation of the antitumor efficacy, pharmacokinetics, and pharmacodynamics of the histone deacetylase inhibitor depsipeptide in childhood cancer models in vivo.

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 x 3 i.v. repeated q21d for a total of two cycles) to scid mice bearing 39 independently derived childhood tumors (9 brain tumors, 11 kidney 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 one Wilms' 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/m2 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 (Ser473). 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.

In vivo evaluation of ixabepilone (BMS247550), a novel epothilone B derivative, against pediatric cancer models.

PURPOSE: Vinca alkaloids, agents that cause depolymerization of microtubules, are highly active in treatment of many pediatric cancers. In contrast, taxanes, agents that stabilize microtubules, are far less effective against the same cancer types. The purpose of the current study was to evaluate the antitumor activity of ixabepilone, an epothilone B derivative representing a new class of microtubule-stabilizing antimitotic agent in a wide variety of pediatric solid tumor models. EXPERIMENTAL DESIGN: Ixabepilone was administered i.v. every 4 days for three doses to scid mice bearing s.c. human rhabdomyosarcoma (three lines), neuroblastoma (four), Wilms' tumors (six), osteosarcoma (four), or brain tumors (seven). Tumor diameters were measured weekly, and tumor growth or regressions were determined. Pharmacokinetic studies were done following a single administration of drug at the maximum tolerated dose (MTD) level (10 mg/kg). RESULTS: At the MTD (10 mg/kg), ixabepilone induced objective responses (all tumors in a group achieved > or = 50% volume regression) in three of three rhabdomyosarcoma lines, three of five neuroblastomas, six of seven Wilms' tumor models, two of six osteosarcoma, and four of eight brain tumor models. However, the dose-response curve was steep with only 2 of 19 tumors models regressing (> or = 50%) at 4.4 mg/kg. In comparison, paclitaxel administered at the MTD on the same schedule failed to induce objective regressions of three tumor lines that were highly sensitive to treatment with ixabepilone. Pharmacokinetics following single i.v. administration of ixabepilone at its MTD (10 mg/kg) were biexponential with C(max) of 12.5 micromol/L, elimination half-life of 19.2 hours, and total area under the curve of 5.8 micromol/L-h. The achieved drug exposure of ixabepilone at this efficacious MTD dose level in mice is similar to those achieved in patients given the recommended phase II dose of 40 mg/m2 by either 1- or 3-hour infusion every 3 weeks, a regimen that has shown significant anticancer activity in phase II clinical trials in adult patients. CONCLUSIONS: Administered at doses ranging from 66% to 100% of its MTD in mice, the epothilone B derivative ixabepilone shows broad spectrum activity against a panel of pediatric tumor xenograft models. Pharmacokinetic analysis indicates that the systemic ixabepilone exposure achieved in mice at its MTD is similar to that achieved in patients at the recommended phase II dose of 40 mg/m2 administered every 3 weeks. Importantly, the present results showed a clear distinction in sensitivity of pediatric solid tumors to this epothilone derivative compared with paclitaxel.