Faculty Collaboration Database

Comparing histone deacetylase inhibitor responses in genetically engineered mouse lung cancer models and a window of opportunity trial in patients with lung cancer. Mol Cancer Ther 2013 Aug;12(8):1545-55

Date

05/21/2013

Pubmed ID

23686769

Pubmed Central ID

PMC3742691

DOI

10.1158/1535-7163.MCT-12-0933

Scopus ID

2-s2.0-84882267461 (requires institutional sign-in at Scopus site)   22 Citations

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.

Author List

Ma T, Galimberti F, Erkmen CP, Memoli V, Chinyengetere F, Sempere L, Beumer JH, Anyang BN, Nugent W, Johnstone D, Tsongalis GJ, Kurie JM, Li H, Direnzo J, Guo Y, Freemantle SJ, Dragnev KH, Dmitrovsky E

Author

David Johnstone MD Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Aged
Animals
Antineoplastic Agents
Apoptosis
Cell Cycle
Cell Line, Tumor
Cell Proliferation
Cyclin D1
Cyclin E
Disease Models, Animal
Dose-Response Relationship, Drug
Female
Histone Deacetylase Inhibitors
Humans
Hydroxamic Acids
Lung Neoplasms
Male
Mice
Mice, Transgenic
Middle Aged
Neoplasm Staging
Oncogene Proteins