Mechanisms of sensitivity in primary hematopoietic tumors and tumor lines to a novel HDAC inhibitor PCI-24781. Free

678

Histone deacetylase (HDAC) inhibitors are a new class of anticancer drugs now being studied in various clinical trials. PCI-24781 (formerly CRA-024781) is a novel HDAC inhibitor that is in phase I clinical trials in patients with solid and hematopoietic malignancies. In this study we show that PCI-24781 inhibits growth and induces apoptosis in a variety of hematopoietic cell lines derived from B-cell, T-cell and myeloid malignancies. Growth inhibition and apoptosis were noted at drug concentrations ≤ 0.125 µM and were accompanied by known biochemical markers of HDAC inhibition including histone and tubulin hyperacetylation. PCI-24781 was also active in murine xenograft models of hematopoietic disease. PCI-24781 has favorable pharmacokinetic and pharmacodynamic profiles in animal models and in humans. To demonstrate the potential clinical utility of PCI-24781 in hematologic tumors, primary leukemia samples were isolated from patients and screened for resistance to PCI-24781-induced growth arrest in vitro. Of these 19 primary samples (10 acute myelogenous leukemia (AML) and 9 acute lymphocytic leukemia (ALL)), some of which were derived from patients who had failed standard therapy, none was resistant to PCI-24781 at 0.5 µM and only 2 (1 AML and 1 ALL) were considered resistant at 50 nM. Gene expression analysis using DNA microarrays on these primary tumor samples revealed alterations of gene expression consistent with HDAC inhibition and defined potential pathways of activity for this compound in these tumors. Several of these pathways were analyzed biochemically and we show here that despite many commonalities, different mechanisms for induction of apoptosis are operative in different cell lines and primary tumor specimens. These results demonstrate that the novel HDAC inhibitor PCI-24781 is highly active in hematopoietic tumor-derived cell lines and in vivo preclinical models. Furthermore, the high sensitivity of primary leukemic cells to treatment with PCI-24781 in vitro coupled with the predicted pharmacokinetics in humans suggests that patients with hematopoietic malignancies, particularly AML and ALL, would be responsive to treatment with PCI-24781 in the clinic.