TY - JOUR
T1 - Comparing histone deacetylase inhibitor responses in genetically engineered mouse lung cancer models and a window of opportunity trial in patients with lung cancer
AU - Ma, Tian
AU - Galimberti, Fabrizio
AU - Erkmen, Cherie P.
AU - Memoli, Vincent
AU - Chinyengetere, Fadzai
AU - Sempere, Lorenzo
AU - Beumer, Jan H.
AU - Anyang, Bean N.
AU - Nugent, William
AU - Johnstone, David
AU - Tsongalis, Gregory J.
AU - Kurie, Jonathan M.
AU - Li, Hua
AU - Di Renzo, James
AU - Guo, Yongli
AU - Freemantle, Sarah J.
AU - Dragnev, Konstantin H.
AU - Dmitrovsky, Ethan
PY - 2013/8
Y1 - 2013/8
N2 - 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. Mol Cancer Ther; 12(8); 1545-55.
AB - 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. Mol Cancer Ther; 12(8); 1545-55.
KW - Aged
KW - Animals
KW - Antineoplastic Agents/administration & dosage
KW - Apoptosis/genetics
KW - Cell Cycle/genetics
KW - Cell Line, Tumor
KW - Cell Proliferation/drug effects
KW - Cyclin D1/genetics
KW - Cyclin E/genetics
KW - Disease Models, Animal
KW - Dose-Response Relationship, Drug
KW - Female
KW - Histone Deacetylase Inhibitors/administration & dosage
KW - Humans
KW - Hydroxamic Acids/administration & dosage
KW - Lung Neoplasms/drug therapy
KW - Male
KW - Mice
KW - Mice, Transgenic
KW - Middle Aged
KW - Neoplasm Staging
KW - Oncogene Proteins/genetics
KW - Vorinostat
UR - http://www.scopus.com/inward/record.url?scp=84882267461&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-12-0933
DO - 10.1158/1535-7163.MCT-12-0933
M3 - Article
C2 - 23686769
AN - SCOPUS:84882267461
SN - 1535-7163
VL - 12
SP - 1545
EP - 1555
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 8
ER -