Abstract 342: Murine transgenic lung cancer models guide a proof of principle histone deacetylase inhibitor trial in lung cancer patients
Authors: Ma Tian , Galimberti Fabrizio , Erkmen Cherie P. , Memoli Vincent , Nugent William , Rigas James , Johnstone David , Li Hua , DiRenzo James , Freemantle Sarah , Dragnev Konstantin , Dmitrovsky Ethan 
Published: June 2012

Abstract
Lung cancer is the most common cause of cancer mortality in the United States. New treatments for lung cancer are therefore needed. We previously engineered murine transgenic cyclin E models that recapitulated frequent features of lung cancers in patients. These included chromosome instability, hedgehog pathway and cyclin D1 activation as well as single or multiple pre-malignant and malignant (adenocarcinoma) lung lesions. Metastases were also observed. Cell lines (ED-1 and ED-2) were derived from these murine lung cancers. After tail vein injection of ED-1 or ED-2 cells into syngeneic FVB mice, neoplastic lung lesions form within 1-2 weeks. These models are useful tools to identify promising anti-neoplastic agents. Among a panel of drugs that caused growth inhibition of lung cancer cells and repression of cyclin D1 protein, the histone deacetylase inhibitor (Vorinostat) was found as most potent. Vorinostat treatment caused dose- (1-5μM) and time-dependent (2 and 4 days) growth inhibition and apoptosis induction in murine lung cancer cells. Effects were reversed by washouts of Vorinostat. Similar reversible Vorinostat effects on growth inhibition and apoptosis were observed in human lung cancer cell lines (HOP62, H522 and H23). Vorinostat treatments repressed cyclin D1 and cyclin E proteins, but increased p27 expression in ED-1 cells. Notably, Vorinostat treatments of cyclin E transgenic mice also substantially repressed cyclin D1 expression in pre-malignant and malignant lung tissues. Vorinostat treatment also significantly reduced lung tumor formation (p = 0.047) in FVB mice harboring transplanted syngeneic murine lung cancer cells. To translate studies into the clinic, an Institutional Review Board-approved proof of principle Vorinostat trial was launched for early stage non-small cell lung cancer cases undergoing surgical resection. Patients receive Vorinostat treatments pre-operatively. Post- versus pre-treatment biopsies will be scored for changes in immunohistochemical profiles of cyclin D1, cyclin E, p27, and ki-67. Trial accrual ends January 2011. Results will then be analyzed with findings reported at this meeting. Taken together, Vorinostat treatments repressed lung cancer cell growth by augmenting apoptosis and reducing cyclin D1 expression. Substantial anti-neoplastic effects of Vorinostat were seen in murine transgenic and transplantable lung cancer models. These studies underscore the value of clinically-relevant murine lung cancer models for guiding clinical trials in lung cancer patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 342. doi:10.1158/1538-7445.AM2011-342