Identifying nuclear hormone receptors, their coregulators, and chromatin remodeling enzymes essential to non-small cell lung cancer (NSCLC) using genetic and pharmalogical approaches.
Nuclear hormone receptors (NRs) bind hormones and induce changes that can culminate in cell proliferation, differentiation, death, or cell motility. In cancers such as breast and prostate cancer, NRs such as the estrogen and androgen receptor, respectively, are known to play important roles in many pro-survival and pro-growth pathways. We hypothesize that NRs and their co-regulators (CoRegs; which interact with NRs to repress or activate them) or chromatin remodelers (which also interact with NRs) play a functional role in lung cancer pathogenesis different from that in normal lung epithelium.
This functional role likely depends on tumor specific oncogenotypes, and may provide tumor-acquired NR/CoReg related vulnerabilities (“synthetic lethality”) that can be therapeutically leveraged. We predict the function of some NRs/CoRegs will be required for tumor cell survival in the context of their oncogenotype and thereby provide a way to “hormonally manipulate” lung cancer in concert with established therapies.
We are investigating the role of NRs and their CoRegs in lung cancer biology utilizing three approaches.
Defining NR/CoReg Lung Cancer Expression Profiles
We have analyzed NR/CoReg mRNA expression in numerous lung cancer specimens, including from the TCGA (The Cancer Genome Atlas). Additionally, we are working to develop a CLIA certifiable, high throughput biomarker platform capable of obtaining mRNA expression signatures from FFPE specimens. The platform has since undergone a rigorous development protocol and has been used to assess NR/CoReg expression levels across a 500+ sample FFPE dataset.
Use RNAi to Systematically Target NR/CoRegs
Our second branch of study began with an RNAi-based systematic functional interrogation of NR/CoReg function in a panel of more than 100 cell lines representative of all clinically relevant facets of lung and breast cancers. Using statistical methods including cluster analysis we generated a robust, novel classification of lung and breast cancers based on their NR/CoReg functional states. Each of these “clades” was demonstrated to be specifically targetable by unique siRNA reagents capable of inducing growth attenuation or stimulation. Further investigation into the mechanisms of action of these siRNA reagents unexpectedly revealed the phenotypes to be largely mediated by miRNA-like seed sequences (off-target effects). We are now working to identify the “true” targets of these siRNA reagents and characterize their anti-cancer potential.
Pharmacologically Interrogate Lung Tumor Panel Using NR Ligands
We have screened a set of 110 NR ligands across the same cell line panel to pharmacologically interrogate these receptors as novel lung cancer targets. We have identified three classes of ligands (ER, GR, and VDR) which exert anti-proliferative phenotypes on specific subsets of the lung cancer cell lines. Of particular note, several of these agents are used routinely in current clinical practice and represent excellent candidates for rapid clinical translation of these findings.