Our current program of research aims to discover effective strategies for individualizing therapy for cancer patients. The proposed program aims to reach this goal through the identification of heritable genetic determinants of outcomes of chemotherapy, both in the laboratory and the clinic. Our lab discovers and tests the biological function of novel germline genetic variants that might serve as markers of severe toxicity and survival. Our main focus is on VEGF-pathway inhibitors. This activity integrates whole-genome strategies with more targeted, gene- and pathway-based, strategies. It requires multidisciplinary efforts that span from the discovery of potential genetic biomarkers to validation of their clinical utility in patients. This effort is truly collaborative.

The research program is built on a series of clinical, epidemiology, and laboratory studies, and is defined by three main themes.

Theme 1: Clinical pharmacogenetic and genome-wide investigations in cancer patients

These studies represent a framework for identifying new markers of outcome to be used for prospective clinical testing and for in vitro evaluation of molecular function, as per Theme 2. Genetic data collected from multiple tumors and multiple drugs (with shared toxicities, metabolic pathways, and similar mechanisms) create a platform for testable hypothesis to individualize patient care.

Candidate gene, pathway-based, and genome-wide association studies are ongoing and planned. Candidate genes studies include genotype-directed clinical trials in colorectal cancer patients. Pathway-based studies include sorafenib pharmacogenetic studies in renal cell carcinoma patients. Genome-wide association studies (GWAS) include a study in pancreatic cancer patients receiving gemcitabine and bevacizumab in Cancer and Leukemia Group B. Additional GWAS and interventional studies are planned, and will be run at UNC, as well as in CALGB.

Theme 2: Functional genetics of VEGF-pathway genes

Angiogenesis plays a critical role in tumor development and progression, and the VEGF-pathway is centrally involved with mediating this process. Angiogenesis is a host-mediated process and we hypothesize that clinical cancer outcomes and variable responses to VEGF-pathway inhibitors may be related to common functional variation in VEGF-pathway genes.

Work in our laboratory has characterized human genetic variation in VEGF-pathway genes and identified common germline variants which associate with their expression in cell systems and lung tumor samples. Validated functional variants from this study will represent the foundation for the prospective pharmacogenetic testing of patients treated with VEGF-pathway inhibitors, as per Theme 1. The results of these studies may propose novel biomarkers for clinical investigation and will support the clinical associations of Theme 1. Furthermore, functional VEGF-pathway gene variants may act as prognostic markers for other clinical cancer outcomes and we are currently evaluating such associations.

Theme 3: Genome-wide regulation of gene expression in the human liver

We are studying the genetic regulation of liver gene expression because of the many important functions this organ performs. These functions include protein synthesis and detoxification, amongst many others. The fact that 75% of the 200 most widely prescribed drugs are eliminated from the body through liver metabolism means this work is of particular relevance to the field of pharmacogenetics.

By correlating the mRNA expression of genes in over 200 human livers with genetic variants, at a genome-wide level, our study provides a comprehensive assessment of the heritable component of gene expression variation in this organ. We are expanding this expression quantitative trait loci (eQTL) study to encompass the measurement of protein expression from important pharmacogenetic genes. Other ongoing analyses include the definition of genomic methylation and miRNA expression in the liver. Results from this work will provide a useful resource for UNC faculty and the scientific community as a whole, as they will be made publicly available. They will serve as the knowledge basis for any pharmacogenetic study (like those in Theme 1) to interpret associations with disposition genes, as well as for studies of heritable liver-related traits and diseases.