title: Comparing histone deacetylase inhibitor responses in genetically engineered mouse lung cancer models and a window of opportunity trial in patients with lung cancer.
abstract: Histone deacetylase inhibitor (HDACi; vorinostat) responses were studied in murine and human lung cancer cell lines and genetically engineered mouse lung cancer models. Findings were compared with a window of opportunity trial in aerodigestive tract cancers. In human (HOP62, H522, and H23) and murine transgenic (ED-1, ED-2, LKR-13, and 393P, driven, respectively, by cyclin E, degradation-resistant cyclin E, KRAS, or KRAS/p53) lung cancer cell lines, vorinostat reduced growth, cyclin D1, and cyclin E levels, but induced p27, histone acetylation, and apoptosis. Other biomarkers also changed. Findings from transgenic murine lung cancer models were integrated with those from a window of opportunity trial that measured vorinostat pharmacodynamic responses in pre- versus posttreatment tumor biopsies. Vorinostat repressed cyclin D1 and cyclin E expression in murine transgenic lung cancers and significantly reduced lung cancers in syngeneic mice. Vorinostat also reduced cyclin D1 and cyclin E expression, but increased p27 levels in post- versus pretreatment human lung cancer biopsies. Notably, necrotic and inflammatory responses appeared in posttreatment biopsies. These depended on intratumoral HDACi levels. Therefore, HDACi treatments of murine genetically engineered lung cancer models exert similar responses (growth inhibition and changes in gene expression) as observed in lung cancer cell lines. Moreover, enhanced pharmacodynamic responses occurred in the window of opportunity trial, providing additional markers of response that can be evaluated in subsequent HDACi trials. Thus, combining murine and human HDACi trials is a strategy to translate preclinical HDACi treatment outcomes into the clinic. This study uncovered clinically tractable mechanisms to engage in future HDACi trials.
authors.affiliation: Departments of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, NH, USA.
authors.forename: Tian
authors.initials: T
authors.lastname: Ma
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Galimberti
authors.forename: Cherie P
authors.initials: CP
authors.lastname: Erkmen
authors.forename: Vincent
authors.initials: V
authors.lastname: Memoli
authors.forename: Fadzai
authors.initials: F
authors.lastname: Chinyengetere
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Sempere
authors.forename: Jan H
authors.initials: JH
authors.lastname: Beumer
authors.forename: Bean N
authors.initials: BN
authors.lastname: Anyang
authors.forename: William
authors.initials: W
authors.lastname: Nugent
authors.forename: David
authors.initials: D
authors.lastname: Johnstone
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Tsongalis
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Kurie
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: James
authors.initials: J
authors.lastname: Direnzo
authors.forename: Yongli
authors.initials: Y
authors.lastname: Guo
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Freemantle
authors.forename: Konstantin H
authors.initials: KH
authors.lastname: Dragnev
authors.forename: Ethan
authors.initials: E
authors.lastname: Dmitrovsky
mesh_terms: D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009367:Neoplasm Staging; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D000077337:Vorinostat
chemical_list: D000970:Antineoplastic Agents; C475820:CCNE1 protein, human; D019927:Cyclin E; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D015513:Oncogene Proteins; D019938:Cyclin D1; D000077337:Vorinostat