"Dr. McLeod is one of the pioneers in the field of cancer pharmacogenomics and we are extremely pleased that he has decided to join the faculty,” said Kim Brouwer, PharmD, chair of the division.

Richard Goldberg, MD, associate director of UNC Lineberger, said, “We are very excited to welcome Dr. McLeod to the UNC community. He and his team of scientists are conducting innovative work in the emerging field of personalized medicine. The intellectual environment at UNC and the investment that the University and state of North Carolina are making in this area of inquiry will enable his practical application of this field to clinical patient care.”

McLeod is an internationally recognized expert in the pharmacogenomic analysis of cancer therapeutics. He is the author or co-author of more than 260 peer-reviewed papers, serves on the editorial board of seven scientific journals, and has given three hundred presentations in fourteen countries. He is a member of the Food and Drug Administration Subcommittee on Clinical Pharmacology and is vice chair of the NIH Cancer and Leukemia Group B Pharmacology and Experimental Therapeutics Committee.

"Dr. McLeod will interface immediately with a number of research groups within the Schools of Pharmacy, Medicine, and Public Health; with many other units across campus, and with regional partners across the state," Brouwer said.

“His vision for the field of pharmacogenomics is global and will be high impact for the Division of Pharmacotherapy and Experimental Therapeutics, the School of Pharmacy, the University, and most importantly, for the people of North Carolina, whom we serve."

McLeod completed research fellowship training in cancer pharmacology at St. Jude Children's Research Hospital in Memphis and at the University of Glasgow in Scotland before becoming the director of the clinical pharmacology program at the Beatson Cancer Centre in Glasgow. He then became a senior lecturer in medicine and director of laboratory research for the oncology unit at the University of Aberdeen in Scotland. McLeod returned to the United States in 2000 to accept a position at Washington University in St. Louis, Missouri, where he was a professor in the Departments of Medicine, Pharmacology and Molecular Biology, and Genetics and director of the Siteman Cancer Center Pharmacology Core.

The Eshelman professorships were created as part of the historic $20 million gift made by Fred Eshelman ('72 BSPhar) to the UNC School of Pharmacy in 2003, which was the third largest gift ever received by the University. Eshelman is the School's leading benefactor and is founder and chief executive officer of PPD, a leading global contract research organization providing development services, market development expertise, and compound partnering programs to the pharmaceutical industry. PPD is based in Wilmington. Eshelman has created four $1 million endowed professorships at the UNC School of Pharmacy.

McLeod will be honored with Coriell’s Scientific Award at a reception on May 23 at the Union League of Philadelphia. The institute also presents a humanitarian award and an ambassador award.

As an internationally recognized expert in the field of pharmacogenomics, McLeod has helped identify genetic variations that predispose patients to risk of severe side effects or inadequate benefit from drugs. His research also modified FDA dosing guidelines for warfarin, a blood thinner prescribed to more than two million people in the United States.

The Camden, New Jersey–based Coriell institute is an independent nonprofit research center dedicated to the study of the human genome. The Coriell Personalized Medicine Collaborative research study is seeking to understand the usefulness of genetic risk and pharmacogenomics in clinical decision making and health-care management.

New Pharmacy Professor Seeks to Match the Medicine to the Patient

Howard McLeod, PharmD, wants to help physicians get it right the first time when they select a medicine to treat cancer and other illnesses. He is heading a new research institute at the UNC School of Pharmacy that will find ways to match medicines to the unique makeup of the people needing them.

“In cancer and almost every other area of medicine, there are multiple drugs that work,” McLeod says. “But none of them work more than half the time. So when prescribers are faced with choosing what medicine to give a person, they often go with the drug they know best. And because there is often no way to know with great certainty how the drug may work in that individual, it may not be the one that will benefit the patient most.”

McLeod is the director of the new UNC Institute for Pharmacogenomics and Individualized Therapy, the first of its kind in the United States. The institute will work to create effective therapy and precise treatment options for individual patients suffering from a wide range of conditions. Initial efforts will focus on cancer therapy with planned expansion into cardiovascular disease, psychiatric disorders, and global health.

When a drug goes through clinical trials, its effectiveness and side effects are determined based on a large population. However, that information only tells individual patients what is possible. It does not tell them what their own experience is likely to be. There are dramatic differences among people in their reaction to a particular medicine, McLeod says.

“If individual patients knew they had twice the risk of a side effect as the average person, they could at least use that information to decide if the medicine is worth it to them or not,” he says.

In the near-term McLeod is less interested in perfection where everyone gets the best medicine 100 percent of time, but he expects to see incremental advancements that will improve health care in both the short and long run.

“When we talk about individualized therapy, we’re just talking about getting it right more often than we get it wrong,” he says. “The goal is not to hit a grand slam every time. It’s to get on base. And if we happen to get around to home, fantastic.”

For example, more than 2 million people in the US take the blood thinner warfarin. It is the textbook example of a drug with what pharmacists call a “narrow therapeutic index,” McLeod says.

“Give a little bit too much, and people bleed,” he says. “Give a too little, and they clot. You have to get it just right.”

There are entire clinics devoted to getting people on the right dose of warfarin, McLeod says. It is a roller coaster of trial and error before the right amount is identified. But based on new genetic discoveries, the Food and Drug Administration is issuing revised guidelines specifying that information present in two genes will affect the dose given to the patient.  This is the third recent example where Dr McLeod has contributed to changes in the FDA treatment recommendations. “Progress is occurring; genetic information is improving the use of medicines in our lifetime.”

Howard McLeod, PharmD

Dr. Howard McLeod recently joined UNC as the Fred Eshelman Distinguished Professor of Pharmacy and professor of medicine. He is also a member of the Lineberger Comprehensive Cancer Center. He is an internationally recognized expert in the pharmacogenomic analysis of cancer treatments and comes to UNC from Washington University School of Medicine in St. Louis, MO. He is the author or coauthor of more than 260 scientific articles and is a member of the FDA Subcommittee on Clinical Pharmacology. He serves on the Scientific Program and Cancer Research Committees for the American Society for Clinical Oncology and is on the editorial board for seven scientific journals. Dr McLeod is a principal investigator in the National Institutes of Health Pharmacogenetics Research Network.

Pharmacogenomics is a new field exploring how the information in our genes influences our response to drugs. and involves the integration of knowledge of pharmacology with modern advances in genome analysis. Knowledge gained this way is changing the use of many anticancer agents by enabling scientists to identify patients who are at risk for adverse reactions or those who are likely to benefit from a particular treatment.

Dr. McLeod is currently working with the large national clinical trials groups—such as Cancer and Leukemia Group B—to confirm that findings from small institutional studies will actually translate into better therapy across the nation. Most large CALGB studies now collect a specific blood sample for DNA analysis as part of the trial.

He and colleagues have already identified specific genetic components of several drugs that have lead to the FDA changing the drug package inserts to identify patient groups that are genetically predisposed to risk of severe side effects or inadequate benefit.  This has included drugs used to treat advanced colorectal cancer (Irinotecan), solid tumors (5-FU) and childhood leukemias (thiopurines such as mercaptopurine).

McLeod's specialty is pharmacogenomics, the science of matching medicines to the unique genetic makeup of a patient, or as McLeod say, "getting the right drug to the right person at the right time." The ad focuses on his work with breast cancer patients and the drug tamoxifen, which kills cancer cells. Oncologists were calling McLeod and asking him why the regular dose of tamoxifen wasn’t having a positive effect on their patients. In studying the women’s genes, McLeod and his team discovered that approximately half of breast cancer patients do not respond to the typical dose. This group needs a dose specialized just for them. McLeod's work led to the FDA changing dosing recommendations for the drug.

You can read more stories like this at one.unc.edu.  You can view the TV spot featuring McLeod by clicking on the video below.

The UNC Institute for Pharmacogenomics and Individualized Therapy has named Kevin Long as the director of its pharmacoinformatics facility.

The new pharmacoinformatics facility, which is based in the UNC Eshelman School of Pharmacy, has been created to develop resources for assessing drug-gene relationships, performing computational pharmacology analysis and providing IT platforms for pharmacogenomics studies.

As the director, Long will provide overall strategic leadership and management in planning and directing applications development and also design and implement physical databases.

Long received his bachelor’s degree in electronics engineering technology at the DeVry Institute of Technology and has more than 15 years of pharmaceutical development experience. He comes to the institute from GlaxoSmithKline, where he served as global manager of bioinformatics for eight years, most recently managing the development of high-throughput systems that included genome-wide association data collection and analysis, custom high-throughput genotyping systems, genotyping assay design, and sequencing data collection for use in GSK’s pharmacogenetic research around the world.

The first presentation will be delivered by Laura Panattoni, a lecturer at the University of Auckland Business School. Her paper is titled "Personalised thienopyridine therapy: the cost effectiveness of genetic testing for CYP2C19 variants to guide treatment in patients with acute coronary syndromes."

The second paper, to be presented by Daniel J. Crespin, MSPH, of the Gillings School of Global Public Health , is titled "Ticagrelor versus Genotype-Driven Antiplatelet Therapy for Secondary Prevention after Acute Coronary Syndrome: A Cost-Effectiveness Analysis."

The UNC Institute of Pharmacogenomics and Individualized Therapy will present a seminar by Tim Wiltshire, PhD, an associate professor in the Division of Pharmacotherapy and Experimental Therapeutics, on Tuesday, September 8. The seminar is titled "Genetic variation in mice: modeling disease, pharmacogenetics, and basic biology". The presentation will be held from 4:00 to 5:00 p.m. and will be live-streamed below. Scroll down for the slideshow accompanying the seminar.

Accompanying Slideshow:

Craig Lee discusses his study

Craig Lee, PharmD, PhD

Scientists at the UNC Eshelman School of Pharmacy at the University of North Carolina at Chapel Hill have discovered that increasing levels of a certain enzyme in blood vessels can lower blood pressure, at least in mice, which could bode well for a new class of drugs currently in phase II clinical trials.

Investigators Craig Lee, PharmD, PhD, and Darryl Zeldin, MD, demonstrated that high levels of the enzyme cytochrome P450 cause mice to produce more of a substance called epoxyeicosatrienoic acid, or EET, which relaxes blood vessels and lowered blood pressure by 40 percent in the test groups. Their findings, “Endothelial Expression Of Human Cytochrome P450 Epoxygenases Lowers Blood Pressure And Attenuates Hypertension-Induced Renal Injury In Mice,” have been published online in the FASEB Journal of the Federation of American Societies for Experimental Biology. A new class of blood-pressure drugs called soluble epoxide inhibitors, or sEH, that increase EETs are undergoing human trials.

"This study adds to our understanding of the P450-EET pathway and its role in lowering blood pressure," Lee says. "Prior studies have shown that manipulating EET levels, particularly in kidney cells, affects blood pressure. What’s novel about our approach is that we were able to lower blood pressure by increasing EET levels in the endothelial cells that line blood vessels. It is my hope that this new information will lead to new and better treatments for hypertension and other conditions affected by blood vessel function."

Lee used a novel mouse model in this study that he created while working as a graduate student with Zeldin at the National Institute of Environmental Health Sciences. These mice have been genetically modified to produce large amounts of certain human versions of the P450 enzyme, specifically CYP2J2 and CYP2C8. When exposed to substances that raise blood pressure, the P450 mice had lower blood pressure and less damage to their kidneys than did a normal group of mice. High blood pressure can harm the kidneys and is a leading cause of kidney failure.

While this study focused on hypertension, Lee says his primary interest in the P450 pathway is in exploring how its role in regulating blood vessel function affects inflammation.

"Vascular inflammation is a key process in the development and progression of cardiovascular disease," Lee says. "Studies in these mice will further our understanding of the role of the P450-EET pathway in this process, and help determine if increasing EETs may be a new and effective way to slow the inflammatory process in blood vessels. This could lead to new treatment strategies for patients with cardiovascular disease."

Lee is an assistant professor in the Division of Pharmacotherapy and Experimental Therapeutics. Zeldin is an adjunct professor in the Division of Pharmacotherapy and Experimental Therapeutics and acting clinical director of the NIEHS Division of Intramural Research.

The other coauthors of the paper are Matthew L. Edin, Julie Foley, Laura M. DeGraff, J. Alyce Bradbury, Joan P. Graves, Fred B. Lih, James Clark, Page Myers, A. Ligon Perrow, and Kenneth B. Tomer of the Division of Intramural Research, National Institute of Environmental Health Sciences; Alison Kannon of the Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy; John D. Imig and Adrienne N. Lepp of the Department of Physiology, Medical College of Wisconsin; Oline K. Ronnekleiv and Nabil J. Alkayed of the Department of Physiology and Pharmacology and Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University; and John R. Falck. Department of Biochemistry, University of Texas Southwestern Medical Center.

T. Don Marsh, PharmD, FASHP, associate director of medical affairs at Kos and former director of pharmacotherapy at the Mountain AHEC, has been instrumental in securing the funding for the program, says assistant professor Jo Ellen Rodgers, PharmD. She is one of the residency’s coordinators along with clinical assistant professor Debbie Montague, PharmD.

“There are only a handful of cardiology specialty residencies are available in the U.S.,” Rodgers says. “These residencies are critically important helping us achieve our mission of elevating the quality of patient care for the people of North Carolina.”

The resident provides clinical services on the General Cardiology Service and the Cardiomyopathy/Cardiac Transplant Service at UNC Hospitals as well as in the Heart Failure Clinic at the UNC Heart Center. The resident also teaches in the Clinical Skills Lab at  the School, precepts fourth-year pharmacy students on rotation, and has lectured at the Schools of Pharmacy, Dentistry, and Nursing.

The award provides Theken with a $6,000 annual stipend and is renewable for a total of three years. Theken’s research project is titled “The Role of Cytochrome P450-Mediated Eicosanoid Metabolism in Atherosclerotic Cardiovascular Disease.”

Cytochrome P450 are a metabolic enzyme family that is present throughout the body. Theken is studying the cytochrome P450 pathways responsible for forming epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosateraenoic acid (20-HETE).

“EETs dilate blood vessels and are anti-inflammatory, while 20-HETE constricts blood vessels and promotes inflammation,” Theken says. “My project focuses on how inflammation influences the balance between EETs and 20-HETE in the cardiovascular system and whether these pathways might be therapeutic targets for the treatment of cardiovascular disease.”

Theken entered the PhD program in the School’s Division of Pharmacotherapy and Experimental Therapeutics in 2006 after earning a doctor of pharmacy at the University of Pittsburgh. Her major adviser in DPET is Assistant Professor Craig Lee, PhD.

“They have been devoted partners to our HIV team,” says Charles van der Horst, a professor in the UNC School of Medicine who is a member of the CFID and the director of the Developmental Core at the UNC CFAR.

“They always say yes when e-mailed or called, no matter what time or day, always stepping up to the plate. They exemplify the best of the Carolina tradition—working for the benefit of the people of North Carolina, working as a team, and devoted to their work.”

Corbett, PharmD, BCPS, is a clinical assistant professor in the School’s Division of Pharmacotherapy and Experimental Therapeutics. Kashuba, BScPhm, PharmD, DABCP, is an associate professor in the division.

Both are involved in various HIV-related collaborations at the University, including the UNC CFAR, where Kashuba directs the Clinical Pharmacology and Analytical Chemistry Core. They have worked closely with the CFID in conducting HIV drug research in Chapel Hill and Malawi. Corbett also works in clinical care for HIV patients.

"Amanda and Angela have helped us understand why individual patients are not responding to therapy by helping us understand drug-drug interactions and by measuring drug levels in these patients to help optimize their treatment," says Joseph Eron, director of the UNC AIDS Clincal Trials Unit.

In addition, Corbett and Kashuba have mentored high school and college students on short-term projects and helped students and professionals in pharmacy and medicine.

“They have both been instrumental in guiding the careers of many others, including other pharmacists, PharmDs, medical students, and physicians,” says Kristine Patterson, a clinical assistant professor in the UNC School of Medicine who has worked closely with Corbett and Kashuba. “They are unselfish in these endeavors.”

The annual award is named for a widely admired UNC psychiatric nurse practitioner who, before her death, helped HIV patients and clinicians cope in the early days of the AIDS epidemic.

The award was established in 1986 to honor a young scientist for accomplishments in the field of clinical pharmacology achieved early in his/her career.

The goal of the Leon I. Goldberg Young Investigator Award is to encourage and recognize young scientists active in the field of clinical pharmacology.

Kashuba has made significant contributions regarding the clinical pharmacology of antiretroviral agents used in the treatment of HIV infection. During her ten years at UNC, she has published more than seventy peer-reviewed manuscripts, eighty scientific abstracts and nine book chapters. Her papers have appeared in some of the most highly regarded journals in the field, including field, including Clinical Pharmacology and Therapeutics, AIDS, Journal of Acquired Immune Deficiency Syndrome, and Annals of Internal Medicine.

Kashuba has received more than $5 million dollars in grant support as principal investigator. She is recognized for her scientific achievements in antiretroviral drug pharmacology, and contributing important information to the literature regarding drug-drug and drug-cytokine interactions. In 2003, she received K23 award from NIAID to support her work in rational antiretroviral selection for pre- and post-exposure prophylaxis of HIV infection.

Since 2004, she has served as director of the Clinical Pharmacology/Analytical Chemistry Core of the UNC Center for AIDS Research. She is an associate professor in the Division of Pharmacotherapy and Experimental Therapeutics.

Kashuba will receive the award at the ASCPT Annual Meeting in Washington, D.C. in March 2009.

Reported by the UNC Institute for Global Health and Infectious Diseases

“We know that administering large doses of HIV drugs in animal models can prevent infection, but this information doesn’t directly help us prevent infections in people,” she says. “In this particular case, the doses being used in animals may be too toxic for people.”

“We need to make more  informed progress toward protecting people, and it’s time we changed the paradigm.”

In support of this goal, the National Institute of Allergy and Infectious Diseases award a grant to the UNC Eshelman School of Pharmacy worth up to $2.17 million over three years. Kashuba is the principal investigator on the grant, which is entitled, “Preventing HIV Infection in Women: Targeting Antiretrovirals to Mucosal Tissues.” She is the director of the UNC Center for AIDS Research Clinical Pharmacology and Analytical Chemistry Core and an associate professor in the Division of Pharmacotherapy and Experimental Therapeutics.

Kashuba plans to determine exactly how much of a drug is needed to protect the mucosal surfaces through which HIV is typically contracted, and to build mathematical models that will predict optimal drug regimens and dosing strategies for HIV prevention. Kashuba has assembled a multidisciplinary team of clinicians and researchers to achieve this goal, including those specializing in infectious diseases, virology, pathology, gynecology, gastroenterology, pharmacometrics, analytical chemistry, regulatory environments, and clinical trial operations.

“This research adds to UNC’s HIV prevention and cure initiatives. It is aimed at using human tissues and safe doses of drugs to protect the uninfected instead of preventing those infected with the virus from transmitting it,” Kashuba says. “We are focused on optimizing the drug and the doses used, and are aiming for 100 percent efficacy using a safe dose.”

Ideally, Kashuba says she would like to maximize effectiveness while getting away from a daily dosing model, which has recently proven to be 40 to 60 percent effective in clinical studies.

“Ultimately, we want to be able to protect women who for many different reasons don’t want to advertise to their partners that they are concerned about HIV,” she says.

Kashuba has also received a $387,618 BRS Shared Instrumentation Grant from the NIH National Center for Research Services to equip her lab with a triple quadrapole mass spectrometer to support her group’s work. The machine is capable of precisely measuring extremely low concentrations of drug in very small samples of cellular material.

Angela Kashuba, PharmD, will direct the preclinical and clinical pharmacology studies as director of the project’s clinical pharmacology core. Kashuba is director of the UNC Center for AIDS Research Clinical Pharmacology and Analytic Chemistry Core and an associate professor in the Division of Pharmacotherapy and Experimental Therapeutics.

Although individuals infected with HIV may effectively control virus levels with antiretroviral drugs and maintain relatively good health, the virus is never fully eliminated from the cells and tissues it has infected. Researchers need to better understand where these reservoirs of HIV are located, how they are established and maintained, and how to eliminate them.

“This year marks the thirtieth anniversary of HIV infection,” Kashuba says. “I believe one of the greatest successes in medicine in this past century has been the ability of antiretroviral therapy to turn this deadly disease into a chronic infection. Yet the fact that we do not have an effective vaccine demonstrates how complex this virus is.”

Previous HIV funding initiatives have focused on prevention and vaccine development.

“This is the first major funding initiative ever to focus on HIV eradication, and we at UNC are excited to lead this important effort,” says David Margolis, MD, professor of medicine and microbiology and immunology in the UNC School of Medicine and principal investigator of this effort. “With this funding, the NIH and the scientific community are saying that finding a cure for AIDS is a realistic goal and should be part of our plan of attack against the epidemic.”

The National Institute of Allergy and Infectious Diseases grant will be administered by the North Carolina Translational and Clinical Sciences Institute at UNC and will be shared among researchers at nine U.S. universities, all of them pioneering researchers in HIV latency. Cofunding is also being provided by the National Institute of Mental Health .

The UNC-led consortium will be one of three groups funded by NIAID under its Martin Delaney Collaboratory initiative. The UNC-led effort will undertake more than a dozen research projects to discover how the virus can remain dormant and virtually invisible, identify drugs and treatments capable of ridding the body of persistent infection and evaluate these new strategies in relevant animal models so that they can be translated into people.

“I am very optimistic about being able to find a functional cure,” Kashuba says. “The collaboration that will occur within this grant this is a great strength and results in a program as a whole that is stronger than the sum of its parts. The exchange of information, technology, and potential products between these investigators and institutions is unprecedented. This is the right time to pursue such an initiative.

The collaboratory also includes an important industrial partner: Merck Research Laboratories in Whitehouse Station, New Jersey. Merck has an outstanding track record in the development of small molecule drugs and other therapies that target viral reservoirs. Merck Research Laboratories will be receiving no federal funds for their contribution to this research.

“This partnering of academia and industry, preclinical and clinical pharmacology, brings strengths and synergies to the collaboratory that wouldn’t be accomplished otherwise,” Kashuba says.

The pharmacology core Kashuba directs is composed of highly skilled analytical scientists within the UNC Eshelman School of Pharmacy, including Craig Sykes, MS, and Nicole White. Julie Dumond, PharmD, a research assistant professor in DPET, will support the pharmacometric activities within the core.

The other universities involved in the UNC-led collaboratory are Case Western Reserve University; Johns Hopkins University; University of California, Davis; University of California, Los Angeles; University of California, San Diego; the Gladstone Institute; University of California, San Francisco; University of Minnesota, and the University of Utah.

Protease is an enzyme that HIV needs in order to make new viruses. When protease is blocked, HIV makes copies of itself that can't infect new cells.

According to Kashuba, many individual drug-drug interaction studies have demonstrated tipranavir's high interaction potential. Kashuba's novel phenotyping approach will help in understanding the basis for these interactions and will form the groundwork for further exploration of potentially important drug interactions.

The title of Kashuba’s project is "Evaluating the Effects of Tipranavir (with Ritonavir) Capsule and Liquid Formulation on Cytochrome P450 and P-glycoprotein Activity Using a Biomarker Cocktail in Healthy Human Volunteers."

“The drug interaction potential in the treatment of HIV infection is unprecedented,” Kashuba says. “Our study is the first of its kind to simultaneously address interaction potential during the early and latter part of therapy and with two different formulations of the compound containing very different excipients.” (Excipients are the inert materials used to create pills and other means of delivering medication.)

This project will provide insight into the mechanisms of drug interactions seen with commonly used ritonavir-enhanced protease inhibitor therapy. The results of this study will be submitted to the Food and Drug Administration for further evaluation.

“The more information we can provide prescribers about the interaction potential of these compounds, the better we will be able to manage the complexities of treating HIV-infected patients,” says Kashuba, who is an associate professor in the Division of Pharmacotherapy and Experimental Therapeutics.