Pharmacy Perspectives - Summer/Fall 2013 - (Page 4)

SUMMER FALL 2013 RESEARCH NEWS Collaborations ACROSS GENERATIONS BY LISA MARSHALL I t was 1959 when a young CU School of Pharmacy grad named Richard Deitrich first took a cow liver from a slaughterhouse, ground it up and dried it to make a powder, and began experimenting with it in hopes of learning more about a barely-known-enzyme called aldehyde dehydrogenase (ALDH). It was “basic science” at its purest, recalls Deitrich, now 82 and a professor emeritus at the Department of Pharmacology in the School of Medicine. “We were interested in finding out what this enzyme does and how it does it.” Over the next five decades Deitrich’s research on ALDH would serve as a critical foundation for better understanding how the body metabolizes alcohol and other toxins. It would also inspire another young scientist - born 6,000 miles away at about the time Deitrich published his first paper – to make his way to CU and take ALDH-research in a new direction: toward finding novel treatments and diagnostic tests for colon cancer and other diseases. “The first papers that I started reading as a graduate student were from this guy in Colorado. I always had a dream to meet him and work with him,” recalls Vasilis Vasiliou, 50, a Greek professor of molecular toxicology at the Skaggs School of Pharmacy and Pharmaceutical Sciences. Vasilis joined Deitrich on the faculty at CU in 1996. Old science spawned new. Collaborations across diverse disciplines blossomed. Technologies rapidly advanced. And last year, Vasiliou published a groundbreaking paper showing for the first time that a specific form of ALDH (ALDH1B1) is present in extremely high concentrations in colon tumors, making it a promising candidate for a biomarker or drug target. Since then, other researchers at CU and beyond have associated various forms of the enzyme with everything from melanoma and breast cancer to cataracts. “The moral of the story here is that, in science, every little piece of information counts,” says Sam Zakhari, PhD, director of the division of metabolism at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), a long-time funder of both Deitrich and Vasiliou’s research. “By understanding alcohol metabolism, we have been able to unravel a lot of other things too. It is a very fertile area now with a lot of applications.” 4 Deitrich also discovered that tissue exposed to certain carcinogens – like dioxin – seemed to light up with ALDH. Taking those findings one step further, scientists began to look at whether cancerous tissue itself showed high levels. The answer is yes. Enter Vasiliou in the mid-1990s and the cancer focus blossomed. Frequently tapping Deitrich’s advice, he used cutting edge technologies including in-vivo-produced enzymes (no more cow livers), high-throughput gene sequencing techniques, and knock-out mouse models – to learn more about the ALDH-cancer link. Vasilis Vasiliou and Richard Deitrich work together in the lab COMING FULL CIRCLE I ronically, Deitrich first began studying ALDH as a postdoc at Johns Hopkins, after a colleague suggested that the enzyme might somehow be linked to tumor cells. “Strangely enough, it did all start out with cancer,” he recalls, sitting next to Vasiliou in the Pharmacy and Pharmaceutical Sciences building. At the time, the cancer link ended up to be a “dead end,” recalls Deitrich. “But eventually it would come full circle.” Deitrich took a job at CU in 1963, and began churning out new information about how “the enzyme” – then believed to be just one, metabolized aldehydes. Ultimately (thanks in part to the Human Genome Project) he would realize that there is not just one ALDH, but 19 different genes that code for different versions – each playing a unique metabolic role. The most common, ALDH-2, is responsible for breaking alcohol in the liver down into more benign acetic acid. (Those who lack the enzyme tend to flush, or get sick when exposed to alcohol. And the drug Antabuse – taken by people trying to quit drinking - works by disabling it.) “When we first started doing these studies, the people interested in aldehyde dehydrogenase could have met in a phone booth, but people got interested because they thought it might be involved in alcoholism,” recalls Deitrich. Meanwhile, he and his colleagues discovered that a different form of ALDH, present in the brain, breaks down byproducts of neurotransmitters such as dopamine and serotonin; and in the eye, other forms help metabolize harmful byproducts of UV radiation. CU Skaggs School of Pharmacy and Pharmaceutical Sciences In January, 2011, he produced a smoking gun, with a study showing 39 out of 40 colon cancer specimens showing high concentrations of ALDH1B1. Whether the enzyme is driving the cancer, or simply a marker has yet to be determined. But either way it is good news, says Vasiliou. He sees a day when physicians can test for ALDH1B1 in tissue, blood, or feces as an adjunct to – or replacement of – a colonoscopy. In the realm of treatment: a “suicide pill” which the defensive enzyme inside cancer cells would devour and metabolize into something that causes the cancer cell to self destruct. In August, a team led by University of Colorado researcher Mayumi Fujita, MD, and collaborated on by Vasiliou, found that melanoma cancer stem cells - which are often resistant to chemotherapy - also express high levels of ALDH. Here too, ALDH may present a promising biomarker or even a drug target used to “re-sensitize cells to chemotherapy.” In recent years, several ALDH enzymes have been found to be abundant in the stem cells that fuel breast, lung, ovarian, prostate, and pancreatic cancers. Meanwhile, Vasiliou is again looking in new directions. With a grant from the National Eye Institute, he is exploring the role that ALDH plays in protecting the cornea from UV light (mice who lack the enzyme tend to be more prone to cataracts). Deitrich couldn’t be more proud. “It’s the lesson that all scientists understand,” he says. “A lot of studies seem to lead nowhere, but you do what you can and occasionally you come up with something that really makes a difference.”

Table of Contents for the Digital Edition of Pharmacy Perspectives - Summer/Fall 2013

Pharmacy Perspectives - Summer/Fall 2013
School News Pharmacist Hunter
Research Collaborations Across Generations
Student News Habitat for Humanity
Graduation - In Depth Coverage
Alumni News Jack of All Trades

Pharmacy Perspectives - Summer/Fall 2013