Abstract 354: Nuclear receptor expression atlas: A theragnostic targets for lung cancer patients
Authors: Yangsik Jeong, Yang Xie, Guanghua Xiao, Luc Girard, Woochang Lee, Carmen Behrens, Ignacio I. Wistuba, John D. Minna, David J. Mangelsdorf
Journal: Cancer Research (2011)

Abstract Introduction: The nuclear receptor (NR) superfamily, comprised of 48 transcription factors that govern complex physiologic and pathophysiologic processes, could represent a unique subset of biomarkers as well as therapeutic targets via selective receptor modulators for lung and other cancers. Aims and Methods: The goal of this initial study was to investigate the association between mRNA expression of the NR superfamily and the clinical outcome of lung cancer patients, and test whether a tumor NR gene signature provided useful information (over available clinical data) for lung cancer patients. Furthermore, diagnostic and therapeutic potential of the NR superfamily was to be assessed using 55 lung cell line as well as publicly available 129 microarray datasets. Results and Conclusions: Using quantitative real-time PCR to study nuclear receptor (NR) expression in 30 microdissected non-small cell lung cancers (NSCLCs) and their pair-matched normal lung epithelium, we found great variability in NR expression among patients’ tumor and non-involved lung epithelium, a strong association between NR expression and clinical outcome, and identified a NR gene signature from both normal and tumor tissues that predicted patient survival time and disease recurrence. This NR signature was validated in two independent microarray datasets derived from 559 resected lung adenocarcinomas, and cross-validated in 130 squamous cell lung cancers. Remarkably, two NRs, short heterodimeric partner (SHP) and progesterone receptor (PR), functioned as single gene predictors of NSCLC patient survival time, including those with stage I disease. Of equal interest, the studies of microdissected histologically normal epithelium from the matched tumors identified expression in normal (but not tumor epithelium) of NGF1B3 and MR as single gene predictors of good prognosis. Thus, NR expression provides a unique prognostic signature for lung cancer patient survival time, particularly for those with early stage disease. In addition, diagnostic potential of the NR superfamily was assessed using 129 Affymetrix HG-U133A microarray samples from which the 48 NR gene signatures were excerpted together with clinical information including a history of smoking. A prediction model using the NR signature was shown to have a significant diagnostic power with overall 84% accuracy of tumor incidence in the smokers. Finally, therapeutic potential of PPARγ, as a proof-of-concept, was preclinically assessed. Both in vitro and in vivo therapeutic evaluation of PPARγ revealed that individual members of the entire NR superfamily can be further developed into molecularly designed therapeutic targets for lung cancer treatment.Taken together, these results highly indicate that the NR superfamily is a potential theragnostic (therapeutic target, diagnostics, and prognostic biomarker) target for 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 354. doi:10.1158/1538-7445.AM2011-354