Human Nuclear Receptors as Molecular Targets in Cancer
Nuclear receptors are ligand modulated transcription factors. These receptors possess conserved DNA and ligand binding domains. Activation occurs when a ligand binds to the receptor and induces a conformation change facilitating recruitment of transcriptional coactivator or corepressor proteins. This ultimately leads to regulation of the expression of downstream target genes.

We have been especially interested in two members of the superfamily of nuclear receptors, FXR and SXR/PXR. FXR, the farnesoid X receptor, when activated by bile acids, serves as a master regulator of cholesterol metabolism in the body. However, little is known of possible other downstream cellular and physiologic effects of the activated FXR. SXR/PXR, steroid X receptor or the xenobiotic receptor, is important in the ability to process xenobiotics. This receptor is activated by many natural and chemical compounds, including bile acids.

The laboratory is interested in the relationship these receptors may have to colonic neoplasms and whether the receptors act as possible links to effect the cellular changes noted to be caused by bile acids. Once the link is established between cancer and a specific nuclear receptor, we may then be able to exploit the pathway by developing synthetic ligands able to modulate the activity of the receptor. This treatment paradigm has already been shown to be clinically relevant and powerful as in the case of tamoxifen and breast cancer.

In addition, the activation of the SXR/PXR affects the metabolism of chemotherapeutic agents, thereby affecting treatment. We have initiated human clinical trials to further elaborate the role of the xenobiotic receptor and its downstream genes in drug metabolism. The results of these trials may change the timing of when therapeutic medications are given.