University of Pittsburgh Cancer Institute (UPCI)

Pharmacogenomics

Vision and Strategy

Pharmacogenomics is a branch of pharmacology that studies the effects of an individual’s genetics on medication response or interactions. The goal is to develop specialized, or personalized, therapies to maximize the effectiveness of cancer treatment, optimized for each patient’s unique genetic makeup.

Recognition of drug-drug interactions and pharmacogenetic differences in drug metabolism, disposition, and susceptibility has increased the need for assays to define relevant polymorphisms and their clinical impact. The UPCI Clinical Pharmacology Analytical Facility (CPAF) provides accessible, economical, comprehensive, and state-of-the-art pharmacology research services that support preclinical and clinical research programs at UPCI and medical institutions nationwide.

The Center for Phamacogenetics

The research focus in the Center for Pharmacogenetics is nuclear receptor-mediated transcriptional regulation of genes that encode drug metabolizing enzymes and transporters.

Nuclear Receptors

Figure 1. Schematic domain structure of a typical nuclear receptor.Nuclear receptors belong to a family of ligand-dependent transcriptional factors (Figures 1 and 2). Activation of nuclear receptors will result in gene regulation at the transcriptional level, which will be further translated into the impact on cellular function and physiology. Nuclear receptors are excellent drug targets, and they also represent a unique and pivotal resource to uncover new regulatory systems that impact both health and human diseases.

Figure 2. Nuclear receptors are ligand-dependent and DNA response element-specific transcription factors.

Nuclear receptor-mediated regulation of drug metabolizing enzymes and transporters

While long studied, the molecular basis of the interactions between the external chemicals (xenobiotics) and the mammalian genome has not been well understood. Such xenobiotics may include clinical drugs and herbal medicines.

Research at The Center for Pharmacogenetics has focused on this environment-host interactions and helps to establish members of the nuclear receptor superfamily as the xenobiotic receptors or xeno-sensors that regulate the expression of xenobiotic enzymes and transporters.

The prototypical xenobiotic receptors include the pregnane X receptor (PXR) and constitutive androstane receptor (CAR). However, the regulatory function of PXR and CAR can also be shared with or impacted by several other nuclear receptors, such as the liver X receptor (LXR), farnesoid X receptor (FXR), and retinoid-related orphan receptor (ROR). The regulation of drug metabolizing enzymes and transporters has great implications in drug metabolism, drug-drug interactions, and drug toxicity.

The endobiotic function of xenobiotic receptors and their target enzymes

In addition to metabolizing drugs, the same enzyme and transporter systems are also responsible for the homeostasis of numerous endobiotic molecules, such as lipids, glucose, sex hormones and bile acids. For these reasons, both the xenobiotic receptors and their target enzymes have broad implications in many human diseases, including hepatobiliary diseases (cholestasis, gallstone disease, fatty liver, and jaundice), endocrine-related disorders (hormone dependent breast cancer and prostate cancer), and metabolic syndrome (obesity and type 2 diabetes) (Figure 3).

Research in the Center for Pharmacogenetics is conducted using a combination of cell cultures and genetically engineered mice that include transgenic, knockout and humanized mice. Since nuclear receptors are ligand-dependent transcriptional factors, we also routinely use pharmacological models, including the use of receptor agonists and antagonists. We are most interested of the physiological and disease relevance of nuclear receptor-mediated gene regulation. We routinely apply various human disease models in our genetic and pharmacological mouse models.

For more information, visit the University of Pittsburgh, School of Pharmacy, Center for Pharmacogenetics