Professor of Medicine
Primary Faculty Department is Medicine
Adjunct Faculty member of Medical & Molecular Genetics
Adjunct Faculty member of Department of Pharmacology & Toxicology
Director, Indiana Institute for Personalized Medicine
Co-Leader, Cancer Prevention & Control Program, IU Melvin & Bren Simon Comprehensive Cancer Center
Discovery & Implementation of Pharmacogenomics to Guide Medication Therapies
I have been leading a variety of efforts to implement genetic testing to guide how physicians select the drug and the dose of drugs for individual patients. One example is using CYP2C19 genetic testing to determine if patients should get clopidogrel therapy. Through the work I have been leading in the IU Precision Health Initiative, we established the genetic test in the clinical laboratory and implemented it in IU Health patients that are considering clopidogrel therapy after receiving a cardiac stent. This testing is now done state-wide in IU Health Cardiac Cather Labs. This was based on work that we have been doing over the last decade. We have published several papers that demonstrate that patients who have genetic variants in their CYP2C19 genes are unable to activate clopidogrel and have poor health outcomes. We have also implemented clinical decision support best practice alerts in the IU Health electronic medical records to alert doctors when patients have genetic results contraindicating the use of clopidogrel therapy. This work was interdisciplinary in that it required the collaborations between scientists with expertise in cardiology, pharmacology, genetics, and informatics. The goal of this work is to personalize the drug therapies for cardiology patients so the right patients get the right drugs. We have also generated evidence and implemented genetic testing for a wide variety of other drugs. For example, we generated some of the original laboratory data that has led to a clinical guideline for using CYP2D6 genetic testing to guide tamoxifen therapy and the development of the drug endoxifen that is now in clinical trials. We have generated in vitro data that identified the appropriate CYP2D6 tests to use for determining the type of genetic variants patients have and that test is now widely used for clinical CYP2D6 testing, including in our clinical laboratory, for a wide variety of drugs. Using genome sequencing, we have identified the likely genetic cause for two rare severe adverse drug events that occurred in patients: one from capecitabine and one from docetaxel. Laboratory work on the capecitabine genetic variant confirmed the impact on gene function and likely role in the toxicity. These have been published as case reports and we are now working to implement this testing in the clinic for cancer patients receiving those drugs. We have discovered the role of small microRNAs in the regulation of the genes that control hepatic drug metabolism; some of these have already been confirmed with clinical trial data. I have also authored 3 different evidence-based clinical guidelines that provide guidance for clinicians on how to use the genetic data to treat patients with antidepressants and pain medications. To generate further evidence for this implementation, I am also the contact PI on a large NIH-funded grant to conduct 4 separate prospective randomized controlled genetic guided clinical trials; we will enroll >2,000 patients in these trials over a ~3 year period. These are just a few of the additional examples of how we generate data in the laboratory, validate in clinical trials, and use this evidence to improve patient care.Because of the complexities of these analyses, they all require collaborations between clinicians, laboratory scientists, and informaticians. Our vision and goal is use individual patients' genetics to reduce the drug therapy-induced toxicities and increase their effectiveness. I have published >180 peer-reviewed manuscripts and through these I have recently been recognized in 2021 by the Web of Science as one of the Highly Cited Researchers who have "demonstrated exceptional influence - reflected through their publication of multiple papers frequently cited by their peers during the last decade".