SUMMARY
Robert B. Diasio, M.D., is principal investigator of the Dihydropyrimidine Dehydrogenase Deficiency Laboratory and former director of Mayo Clinic Comprehensive Cancer Center. His lab research focuses on understanding how genetic factors can affect the efficacy of anti-cancer agents and can also be potential predictors of individuals at risk of severe, and potentially life-threatening, adverse drug toxicities.
Dr. Diasio's primary research focus is on the chemotherapy agent 5-fluorouracil (5-FU), which is prescribed to nearly 300,000 patients annually in the U.S. for the management of colorectal and other cancers. His lab has been instrumental in demonstrating that dihydropyrimidine dehydrogenase (DPD, encoded by the DPYD gene) has a critical role in converting approximately 85 percent of administered 5-FU to inactive metabolites.
The primary goals of Dr. Diasio's research program are directed toward improving the understanding of how genetic factors can alter the expression and function of genes important to 5-FU metabolism and using this information to develop predictive tests for individualizing 5-FU-based chemotherapy to minimize toxicity while maintaining drug efficacy.
Focus areas
- Personalized 5-FU therapy for colorectal cancer. Dr. Diasio's lab is using pharmacogenetic and pharmacogenomic information to develop personalized medicine algorithms for individualized medicine approaches to treating colorectal cancer with chemotherapy containing 5-FU.
- Risk of 5-FU toxicity. Using a combination of clinical, cellular and in vitro biochemical systems, the lab is identifying genetic variations in the DPYD gene — such as single nucleotide polymorphisms, insertion-deletions and splice site variations — that contribute to dihydropyrimidine dehydrogenase (DPD) deficiency and, as such, may be risk factors for adverse 5-FU toxicity.
- Effects of gene regulation on 5-FU therapy. Another research interest of Dr. Diasio's lab is to identify and characterize the mechanisms that control expression of DPD and DPYD (including microRNA and epigenetic mechanisms) and to determine how changes in gene regulation can contribute to altered therapeutic response, adverse 5-FU toxicity, or both.
- Individualized cancer care. The lab is working to develop and study targeted therapies for the treatment of colorectal cancer as a means to further individualize cancer care based on epigenetic, pharmacogenetic, pharmacogenomic and cancer genome information.
Significance to patient care
Clinical studies with patients who had experienced life-threatening toxicity after exposure to 5-FU led to the identification and characterization of the pharmacogenetic syndrome of DPD deficiency.
More recently, Dr. Diasio's laboratory performed a comprehensive functional analysis of DPYD variants for relevance to clinical 5-FU toxicity. These studies have paved the way to develop genetic tests to predict DPD deficiency and to develop better personalized medicine strategies to treat colorectal cancer.
Professional highlights
- Member, editorial board, Clinical Pharmacology & Therapeutics journal, 2011-present; Clinical Cancer Research journal, 1998-2012; Journal of Clinical Oncology, 2005-2010; Cancer Research journal, 1997-2010
- Fellow, American Association for the Advancement of Science, 2008-present
- Co-chair, National Clinical Trials Network Working Group (NCTN), National Cancer Institute (NCI), 2012-2014
- Member, Board of Scientific Advisors, NCI, 2008-2013
- William J. and Charles H. Mayo Professor II, 2007