A Phase I/II Clinical Trial of PXD101 in Combination with Idarubicin in Patients with AML Not Suitable for Standard Intensive Therapy

The pharmacodynamics investigations in PXD101-CLN-15 included correlation of response with gene expression (n=13). Gene expression profiling based on 13 patients (4 responders and 9 non- responders) revealed a strong gene expression pattern associated with the response to belinostat. 1905 genes were significant at the p<0.05 level of the univariate test. MLL(p=0.0000769), a gene well known to play a crucial role in leukemogenesis via epigenetic deregulation, was among the top 20 candidates. Of these, differential expression of TP53(p=0.0001817) is also of special interest as histone deacetylase have been shown to modulate p53 transcriptional activity through regulation of p53-DNA binding activity. An additional interesting candidate was CCT5(p=0.000135), chaperonin containing TCP1, subunit 5 (epsilon), a known interactor of HDAC3 and HDAC5 (see http://www.ncbi.nlm.nih.gov/gene/22948) that encodes for a molecular chaperone that is a member of the chaperonin containing TCP1 complex (CCT). GO (gene ontology) class comparison analysis shows a significant enrichment of gene ontologies including categories associated with epigenetic regulation such as the GO category “histone methyltransferase activity” (comprising e.g. MLL, ASH2L, MEN1, and SUZ12) and “histone deacetylase activity” (comprising e.g. HDAC7, HDAC2, SIRT5, and HDAC2). The gene signature provides insights into the molecular deregulation prone to restoration of epigenetic deregulation, and the respective gene expression pattern also harbors predictive information as demonstrated by the blinded belinostat response prediction based on an in vitro cell line derived predictor. All samples were obtained from untreated patients at the time of diagnosis. Cells used for microarray analysis were collected from the purified fraction of mononuclear cells after Ficoll density centrifugation. Routine diagnostic algorithms, including the characterization of molecular markers are performed.