title: Biomarkers of histone deacetylase inhibitor activity in a phase 1 combined-modality study with radiotherapy.
abstract: BACKGROUND
  Following the demonstration that histone deacetylase inhibitors enhanced experimental radiation-induced clonogenic suppression, the Pelvic Radiation and Vorinostat (PRAVO) phase 1 study, combining fractionated radiotherapy with daily vorinostat for pelvic carcinoma, was designed to evaluate both clinical and novel biomarker endpoints, the latter relating to pharmacodynamic indicators of vorinostat action in clinical radiotherapy.
  
  
  METHODS
  Potential biomarkers of vorinostat radiosensitizing action, not simultaneously manifesting molecular perturbations elicited by the radiation itself, were explored by gene expression array analysis of study patients' peripheral blood mononuclear cells (PBMC), sampled at baseline (T0) and on-treatment two and 24 hours (T2 and T24) after the patients had received vorinostat.
  
  
  RESULTS
  This strategy revealed 1,600 array probes that were common for the comparisons T2 versus T0 and T24 versus T2 across all of the patients, and furthermore, that no significantly differential expression was observed between the T0 and T24 groups. Functional annotation analysis of the array data showed that a significant number of identified genes were implicated in gene regulation, the cell cycle, and chromatin biology. Gene expression was validated both in patients' PBMC and in vorinostat-treated human carcinoma xenograft models, and transient repression of MYC was consistently observed.
  
  
  CONCLUSIONS
  Within the design of the PRAVO study, all of the identified genes showed rapid and transient induction or repression and therefore, in principle, fulfilled the requirement of being pharmacodynamic biomarkers of vorinostat action in fractionated radiotherapy, possibly underscoring the role of MYC in this therapeutic setting.
authors.affiliation: Department of Oncology, Akershus University Hospital, Lørenskog, Norway ; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Anne Hansen
authors.initials: AH
authors.lastname: Ree
authors.affiliation: Department of Tumor Biology, Oslo University Hospital - Norwegian Radium Hospital, Oslo, Norway ; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
authors.forename: Marie Grøn
authors.initials: MG
authors.lastname: Saelen
authors.affiliation: Department of Oncology, Akershus University Hospital, Lørenskog, Norway.
authors.forename: Erta
authors.initials: E
authors.lastname: Kalanxhi
authors.affiliation: Department of Genes and Environment, Norwegian Institute of Public Health, Oslo, Norway.
authors.forename: Ingrid H G
authors.initials: IH
authors.lastname: Østensen
authors.affiliation: Department of Tumor Biology, Oslo University Hospital - Norwegian Radium Hospital, Oslo, Norway.
authors.forename: Kristina
authors.initials: K
authors.lastname: Schee
authors.affiliation: Department of Oncology, Akershus University Hospital, Lørenskog, Norway.
authors.forename: Kathrine
authors.initials: K
authors.lastname: Røe
authors.affiliation: Department of Tumor Biology, Oslo University Hospital - Norwegian Radium Hospital, Oslo, Norway.
authors.forename: Torveig Weum
authors.initials: TW
authors.lastname: Abrahamsen
authors.affiliation: Department of Oncology, Oslo University Hospital - Norwegian Radium Hospital, Oslo, Norway.
authors.forename: Svein
authors.initials: S
authors.lastname: Dueland
authors.affiliation: Department of Tumor Biology, Oslo University Hospital - Norwegian Radium Hospital, Oslo, Norway ; Department of Gastroenterological Surgery, Oslo University Hospital - Norwegian Radium Hospital, Oslo, Norway.
authors.forename: Kjersti
authors.initials: K
authors.lastname: Flatmark
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015415:Biomarkers / Q000378:metabolism*; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D056572:Histone Deacetylase Inhibitors / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000378:metabolism / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D046228:Microarray Analysis; D008875:Middle Aged; D010386:Pelvic Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D013997:Time Factors; D000077337:Vorinostat
chemical_list: D015415:Biomarkers; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D011838:Radiation-Sensitizing Agents; D000077337:Vorinostat