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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE39363 | GEO | 2014/12/31

SECONDARY ACCESSION(S): PRJNA170717

REPOSITORIES: GEO

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Project description:Histone deacetylases (Hdac) remove acetyl groups from proteins, influencing global and specific gene expression. Hdacs control inflammation, as shown by Hdac inhibitor-dependent protection from DSS-induced murine colitis. While tissue-specific Hdac knockouts show redundant and specific functions, little is known of their intestinal epithelial cell (IEC) role. We have shown previously that dual Hdac1/Hdac2 IEC-specific loss disrupts cell proliferation and determination, with decreased secretory cell numbers and altered barrier function. We thus investigated how compound Hdac1/Hdac2 or Hdac2 IEC-specific deficiency alters the inflammatory response. Floxed Hdac1 and Hdac2 and villin-Cre mice were interbred. Compound Hdac1/Hdac2 IEC-deficient mice showed chronic basal inflammation, with increased basal Disease Activity Index (DAI) and deregulated Reg gene colonic expression. DSS-treated dual Hdac1/Hdac2 IEC-deficient mice displayed increased DAI, histological score, intestinal permeability and inflammatory gene expression. In contrast to double knockouts, Hdac2 IEC-specific loss did not affect IEC determination and growth, nor result in chronic inflammation. However, Hdac2 disruption protected against DSS colitis, as shown by decreased DAI, intestinal permeability and caspase-3 cleavage. Hdac2 IEC-specific deficient mice displayed increased expression of IEC gene subsets, such as colonic antimicrobial Reg3b and Reg3g mRNAs, and decreased expression of immune cell function-related genes. Our data show that Hdac1 and Hdac2 are essential IEC homeostasis regulators. IEC-specific Hdac1 and Hdac2 may act as epigenetic sensors and transmitters of environmental cues and regulate IEC-mediated mucosal homeostatic and inflammatory responses. Different levels of IEC Hdac activity may lead to positive or negative outcomes on intestinal homeostasis during inflammation Total RNAs from the colon of three control and three Hdac2 IEC-specific knockout mice were isolated with the Rneasy kit (Qiagen, Mississauga, ON, Canada).

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

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