Pharmacodynamic Evaluation of the Target Efficacy of SB939, an Oral HDAC Inhibitor with Selectivity for Tumor Tissue

Abstract

SB939 is an oral histone deacetylase (HDAC) inhibitor currently in phase II clinical trials potently inhibiting class I, II, and IV HDACs with favorable pharmacokinetic properties, resulting in tumor tissue accumulation. To show target efficacy, a Western blot assay measuring histone H3 acetylation (acH3) relative to a loading control was developed, validated on cancer cell lines, peripheral blood mononuclear cells (PBMC), and in animal tumor models. Exposure of cells to 60 nmol/L (22 ng/mL) SB939 for 24 hours was sufficient to detect an acH3 signal in 25 mg of protein lysate. AcH3 levels of liver, spleen, PBMCs, bone marrow and tumor were measured in BALB/c mice, HCT-116 xenografted BALB/c nude mice, or in SCID mice orthotopically engrafted with AML (HL-60) after oral treatment with SB939. AcH3 could only be detected after treatment. In all tissues, the highest signal detected was at the 3-hour time point on day 1. On day 15, the signal decreased in normal tissues but increased in cancerous tissues and became detectable in the bone marrow of leukemic mice. In all tissues, acH3 correlated with SB939 dose levels (r 2 ¼ 0.76-0.94).When applied to PBMCs from 30 patients with advanced solid malignancies in a phase I clinical trial, a dose-dependent (10-80 mg) increase in relative acH3 was observed 3-hour postdose on day 1, correlating with C max and AUC of SB939 concentrations in plasma (r ¼ 0.97, P ¼ 0.014). Our data show that the favorable pharmacokinetic and pharmacodynamic properties of SB939 are translated from preclinical models to patients.

Inhibition of acute lethal pulmonary inflammation by the IDO–AhR pathway

“…Consequently, the inhibitory effects of SB939 on IPS were significantly increased compared with SAHA. SB939 is a new orally active hydroxamate-based HDACi that is currently in phase II clinical trials and that potently inhibits class I, II, and IV HDACs with excellent pharmacokinetic properties (42,43). Compared with SAHA, SB939 exhibits increased oral bioavailability and half-life.…”

Phase 1 dose escalation multicenter trial of pracinostat alone and in combination with azacitidine in patients with advanced hematologic malignancies

“…13 In vitro , the AcH3 levels varied significantly among the different subtypes of pracinostat-treated PBMCs, with CD20 + B-lymphocytes showing the highest levels and CD16 + monocytes showing the lowest levels of AcH3. 11 Therefore, AcH3 levels in pracinostat-treated PBMCs are not comparable in patients with hematological malignancies due to the abnormal variation in the percentages of the different hematopoietic cells.…”

“…10 Furthermore, pracinostat, in contrast to vorinostat, has been found to accumulate in tumor tissue and induce a dose-dependent sustained elevation in the histone H3 acetylation (AcH3) levels in mice models of AML and human colorectal cancer. 10, 11 …”

A Phase I, Pharmacokinetic, and Pharmacodynamic Study of Panobinostat, an HDAC Inhibitor, Combined with Erlotinib in Patients with Advanced Aerodigestive Tract Tumors

“…Attempts to establish a correlation between surrogate markers such as histone hyperacetylation in PBMCs and drug efficacy in tumor tissue are not always consistent with measured pharmacokinetic profiles of HDAC inhibitors, as findings can vary from patient to patient (50) and data interpretation poses challenges in the setting of background noise (51). The reasons why PBMCs differ from tumor tissue in their response to HDACI are not completely understood and could be related to insufficient drug penetration particularly in solid tumors due to differences in tissue architecture and haemodynamics.…”

“…The reasons why PBMCs differ from tumor tissue in their response to HDACI are not completely understood and could be related to insufficient drug penetration particularly in solid tumors due to differences in tissue architecture and haemodynamics. Additionally, PBMCs are a mixed population of T cells, B cells, monocytes, and natural killer cells, and it has been shown that each individual cell population contributes differently to the histone acetylation detected after treatment with HDACi (51) indicating that histone acetylation levels in PBMCs after treatment with an HDACi might not be directly comparable across patients. In this study, we hypothesized that given its homogeneity, mature adipose tissue might be an appropriate surrogate tissue to assess the pharmacodynamic efficacy of HDACi treatment that would allow direct comparison of drug response across patients and studies.…”