The Department of Medicine is firmly committed to excellence in translational research and its promise to impact patient care. For years, the Department has been at the forefront in developing and delivering personalized medicine (also referred to as precision medicine). Precision medicine enables physicians to identify patients who are more susceptible to certain diseases or specific therapies, and we have made significant contributions and advances in this area during the past year.
Directed by Nancy Cox, PhD, TRIDOM (Translational Research Initiative in the Department of Medicine) is a large-scale sample collection that has enabled investigators to link clinical information on health and disease status and disease progression to biological samples to allow investigators to test a broad range of genomic and proteomic biomarkers. Since its inception in 2005, nearly 11,000 patients have consented to TRIDOM, and there are specimens available on nearly 7,000 patients. Investigators use samples from TRIDOM to generate and test hypotheses regarding genetic predispositions to disease, gene-environment interactions and genetic modifiers of disease. A key future goal is to establish a huge city-wide resource to enable much broader investigations to be conducted “in-silico,” using information from the genotype data (for both common and rare variants) in TRIDOM and combined with information on individuals collected through other biobanks in the city.
Precision medicine enables physicians to identify patients who respond to treatments differently. Within the Center for Personalized Therapeutics (Mark Ratain, MD—director), investigators are translating genomic discovery into improved care by using pharmacogenomic information. A large clinical study called “The 1,200 Patients Project” (Peter O’Donnell, MD—PI) was implemented to explore the feasibility and benefit of incorporating pharmacogenomic testing into clinical practice. To achieve this goal, Dr. O’Donnell has already enrolled 1,017 patients (out of 1,200) to study genetic data to determine a patient’s risk of developing side effects and to provide more information to physicians about drugs, leading to more informed prescribing of medications and allowing for treatments to be chosen and/or dosed based upon each individual’s genetic makeup.
Similarly, Eileen Dolan, PhD, has developed a cell-based approach to identify which patients with ovarian cancer will respond poorly to chemotherapy (See Dolan page 10). Yusuke Nakamura, MD, PhD, has been working to better understand the role of T cell diversity in various disease conditions including cancer and autoimmune diseases. In order to fully characterize the changes or abnormalities in T cell populations, his group performs deep T cell receptor (TCR) sequencing with next-generation sequencers. Studies are currently being carried out in several areas, one of which is bone marrow transplantation. Dr. Nakamura is collaborating with Dr. Michael Bishop on a project to characterize the T cell populations that are specifically turned on in patients who developed acute GVHD after transplant. With the advent of this new technology, Dr. Nakamura’s team is able to determine if there are particular populations of T cells that are activated in patients by examining TCR diversity changes in millions of T cells over time. This type of analysis will lead to an understanding of whether identification of particular TCR sequences is able to help predict and/or monitor patients’ response to therapy, as well as seeing whether specific TCR sequences are predictive of relapse or GVHD.
Barbara Stranger, PhD, is conducting a new initiative for Enhanced GTEx, that will analyze new kinds of data from the tissues collected in the GTEx (Genotype Tissue Expression) project. Dr. Stranger will focus her investigations on generating information on protein levels in high throughput in GTEx tissues to measure the levels of approximately 1500 cell signaling and transcription factor proteins in five unique tissues from 120 individuals. This will enable her to determine whether genome variants associated with protein expression have been previously associated with complex diseases or traits, or other function, and will therefore pinpoint proteins and protein networks that underlie complex human traits and diseases and response to therapy. Dr. Stranger recently augmented her project to enable collection of information on proteins thought to be found at different levels in males and females, as such studies may aid in allowing us to understand sex differences in disease risk and response to therapy. Similarly, Dr. Cox, Dr. Stranger and Andrey Rzhetsky, PhD, are examining sex differences in genome regulation, disease risk and response to therapy (Drs. Stranger and Rzhetsky for the Conte Center studies in autism, bipolar disorder and schizophrenia; and Dr. Cox for studies in pharmacogenomics; and Drs. Stranger and Cox to identify sex-biased regulatory variation in GTEx).
Inflammatory Bowel Disease (IBD)
Researchers in the IBD research group (Eugene Chang, MD—director) are developing new approaches to advance personalized medicine. An example is the development of intestinal organoids derived from stem cells of the gut that can be banked as “live archives” of individual patients. This collection creates opportunities to define more precisely subtypes of IBD that can help inform clinicians on how to tailor interventions and therapies to improve patient outcomes and responses. A second initiative is the development of a capability focused on the discovery of environmental and microbe-derived bioactive factors that impact health and disease. The third initiative involves the application of experimental and computational approaches that can analyze the functional profiles of individual cells and tissue compartments. All three initiatives are aimed to lead to precision medicine tools that can be useful to clinical practice.
Obesity & Cardiovascular Disease
Obesity is strongly associated with insulin resistance and type 2 diabetes, and is an important risk factor for cardiovascular disease. Recent studies indicate that obesity leads to an inflammatory state in metabolic tissues. This metabolic inflammation, or metaflammation, is often defined as low-grade, chronic inflammation that is mediated by specific types of macrophages, termed M1 macrophages. Investigators in the Section of Cardiology (James Liao, MD, and Francis Alenghat, MD, PhD) are determining how a signaling protein, Rho kinase (ROCK), and M1 macrophages can influence chronic inflammatory vascular disease such as atherosclerosis. It is possible that by activating ROCK and/or modulating macrophage phenotype in metabolic tissues, metaflammation and the development of insulin resistance and type 2 diabetes could be prevented. Further studies focusing on metaflammation may help determine which obese patients are at risk for cardiovascular disease.
Faculty in endocrinology and their colleagues continue to make discoveries leading to novel treatments, prevention and potential cures for diabetes, obesity and thyroid disease. The University of Chicago has a longstanding tradition of studies of the genetics of diabetes. As an example, Graeme Bell, PhD, cloned the human insulin gene and showed that a common variation contributes to the development of type 1 diabetes. He and Dr. Nancy Cox showed that mutations in the genes for the glycolytic enzyme, glucokinase, and the transcription factors, HNF-1a, HNF-1b and HNF-4a, caused an early-onset form of diabetes called maturity-onset diabetes of the young or MODY. Work by these investigators and Kenneth Polonsky, MD, showed that these mutations affect insulin secretion and pancreatic beta-cell function. More recently Dr. Bell; Lou Philipson, MD; Siri Greeley, MD, PhD; and Rochelle Naylor, MD; have established the University of Chicago as a world leader in the evaluation and treatment of monogenic diabetes. These investigators have identified novel genes that lead to neonatal diabetes, discovered a new class of insulin gene mutations as a cause of diabetes, and have helped establish sulfonylureas as an alternative to insulin for many patients with neonatal diabetes. Work by this group, along with that of Elbert Huang, MD, has shown that genetic testing is a cost-effective approach for patients with neonatal and other monogenic forms of diabetes. Over the last several years, Dr. Greeley has established a monogenic diabetes web-based registry to enable the evaluation of patients across the globe by the University of Chicago Diabetes Genetics group.
The Department of Medicine remains an internationally recognized center for the diagnosis and care of patients with genetic forms of thyroid dysfunction. Recently Samuel Refetoff, MD, and Alexandra Dumitrescu, MD, PhD, have worked together to expand the spectrum of genetic thyroid disorders to include novel syndromes characterized by defects of thyroid hormone metabolism and transport. They are currently investigating innovative treatment strategies for patients with these disorders, and their group continues to be an international referral center for such patients.
Although precision medicine will likely eventually take hold in many disease areas, the field of oncology is leading the way. Cancer was clearly defined as a genomic disease with significant contributions from Janet Rowley, MD. The catalogue of structural variations, deletions, amplifications, point mutations, gene fusions and the differential expression of genes and isoforms present in malignancies is becoming more and more complete. In parallel, the compendium of targeted oncology agents in development or active use is growing every year. The combination of these two activities is driving the oncology field into the era of precision medicine, in which patients receive treatment that is specifically tailored to the molecular characteristics of their tumor.
In lung cancer research, Ravi Salgia, MD, PhD, and his team are expanding their investigative efforts in precision medicine to evaluate molecular abnormalities in thoracic malignancies. Currently, work includes evaluating molecular aberrations of genes such as EGFR, ALK, ROS1, MET, RET, BRAF and KRAS, among others, and arriving at specific molecularly targeted therapies. Most recently, as an example, they have worked with various investigators internationally to define the role of crizotinib in ALK and ROS1 translocated non-small cell lung cancer. There are a number of unique toxicities that arise from these kinase inhibitors and Dr. Salgia and his team have begun to define them and define their optimal management. This year, the team has also begun to study the role of immunotherapy in thoracic malignancies. Their goal is to integrate clinical characteristics, clinical research, as well as molecular abnormalities to enhance survival of patients with thoracic malignancies while also defining ways to minimize toxicity associated with the various therapies.
Inflammation and Immunology
Marcus Clark, MD (see Clark page 9), and his colleagues in the Knapp Center for Lupus and Immunology Research are applying novel approaches to the study of inflammation in a variety of human diseases. Created in 2009, the NIH-funded Chicago Center of Excellence in Autoimmunity has made substantial progress in providing a collaborative platform for human-focused autoimmune studies in rheumatology, neurology, gastroenterology and nephrology. In particular, their work in lupus, a severe body-wide autoimmune disease for which there are few therapies, is enabling the development of more effective and less toxic therapies.
These examples illustrate success in our pursuit to transform healthcare by bringing the benefits of precision medicine to patients at the University of Chicago Medicine.