All Together Now

To close the gap between science and medicine, researchers and physicians speak with one voice to hasten laboratory discoveries to the patient’s bedside.

by Lori Oliwenstein

Translational medicine—a term that describes a close, back and forth collaboration among scientists and clinicians—travels a two-way street.

Fresh discoveries and medical advances compel scientists and clinicians at the USC/Norris Comprehensive Cancer Center to meet frequently to exchange ideas and information about one another’s work. Researchers at laboratory benches interpret suggestions from physicians who are treating cancer patients to spur development of new drugs and treatments. The ideas are tested—first on cells, then on tissues and finally on patients—providing feedback and data to scientists ready to meet the next challenge.

Translational—or bench-to-bedside—medicine is at the heart of the mission of USC/Norris. It is what sets USC/Norris apart from many other such centers. It is all about closing the gap between science and medicine. It is about teamwork and dialogue. And it is something the center’s dedicated staff does well.

In the world of translational medicine, no scientist—or surgeon, or oncologist or epidemiologist—is an island. “When you have questions, you can walk down the hall, talk to another scientist, get a quick answer, and move on,” says Susan Groshen, Ph.D., professor of preventive medicine at the Keck School of Medicine of USC. “It makes all the difference in the world.”

USC/Norris researchers are not the only people who see the possibilities for bench-to-bedside progress at the Cancer Center. In 2002, the L.K. Whittier Foundation awarded $5.2 million to USC/Norris to establish the L.K. Whittier Foundation Tailored-Therapies Initiative, which funds pilot studies in cutting-edge research with translational potential.

Ite Laird-Offringa, Ph.D., Keck School associate professor of surgery, is one of the many scientists who have benefited from the Whittier Initiative. Her basic-science laboratory—and its wide-ranging collection of collaborators—has been looking for molecular markers of lung cancer that can be detected in the clinic using minimally invasive techniques.

“The Whittier grant is the kind of funding that allows us to do the initial work that is required to get the grants from the National Institutes of Health that will let us take it to the next steps,” she says. “Without programs like the Whittier Foundation provides, we’d never be able to move our research from bench to bedside.”

Gutting tumors

When the USC team of Heinz-Josef Lenz, M.D., Keck School professor of medicine, Robert Ladner, Ph.D., Keck School assistant professor of pathology, and Groshen get together, they are single-minded and focused on their goal to identify the “molecular fingerprints” in tumor cells that will allow them to identify the drugs with the best chance of success against an individual’s tumor.

One of the Cancer Center’s greatest strengths, says Lenz, is that “we have a matrix in which to interact between basic science and clinical research.” But it does not end there. In his translational team, he says, a statistician is always involved in all of the research “to be sure we have a basis for collecting honest, valid data.”

Lenz ticks off a number of ways in which the team has influenced the treatment of gastrointestinal cancers. “We recently found a variation of a critical gene that predicts the response to the chemotherapy drug 5-FU [5-fluorouracil],” he says. In the laboratory, lower levels of this gene—called thymidine synthase, or TS—appear to predict a better response to 5-FU. “So now, we have two ongoing clinical trials to see if this response is true in humans, as well,” Lenz says.

The team is interested in 5-FU for a number of reasons, not the least of which is its history. It was synthesized by Charles Heidelberger, Ph.D., USC/Norris Cancer Center’s director of basic research until his death in 1983. “We like to think of it as one of our drugs,” Groshen says. “Now we just need to learn how to best maximize its efficiency and minimize its toxicity.”

In another project, the team is looking at an enzyme called histone deacetylase, or HDAC, which also seems to be able to put the brakes on the TS gene. “We want to see if we can downregulate TS in patients so that we can make the tumor sensitive again to certain drugs,” Ladner says. To that end, they are working with an HDAC inhibitor to see if they can have an impact on the growth of gastrointestinal tumors.

Lenz says, “We want to find the tumor’s weakness, in order to interfere with the addiction it has” for a certain enzyme or protein that it needs to keep growing.

And for that to happen, collaboration is essential. “Our job is to understand how drugs work, especially the new, targeted agents,” Lenz says. “And that’s only possible for us because we work so very closely together.”

It was this closeness that first brought Ladner to USC/Norris. “This kind of interaction, this level of communication, it’s a gold mine,” he says. “It would never have happened where I was before.”

A translational research team is a dynamic system, Lenz says. “Information flows in all different directions. Data go from Bob’s cell dish to a clinical trial I’m running, and vice versa. Susan helps us to plan up front, so that we don’t waste time or resources.”

Groshen explains: “My job is to look at a study’s design and help them figure out if, at the end of the day, it will provide data that will help them answer their questions. In the process of explaining things to me, it often helps them to be clearer in what they want to do. Talking about it out loud really formalizes their thoughts.”

Says Ladner: “We always wind up with a much better project than any one of us could do alone.” And, of course, the team maintains close relationships with the National Institutes of Health and the National Cancer Institute, which is where they derive much of their funding, and with pharmaceutical industry partners as well.

Vaccine response

Scientists trying to fight cancer by enlisting the immune system in the battle revere the intellectual firepower USC/Norris has in oncology division chief Jeffrey Weber, M.D., Ph.D., the Berle and Lucy Adams Chair in Cancer Research and Keck School associate professor of medicine and molecular microbiology and immunology, and cancer vaccine researcher W. Martin Kast, Ph.D., the Walter A. Richter Chair in Cancer Research and Keck School professor of molecular microbiology and immunology.

Kast provides Weber, as well as other cancer center researchers, with vaccines to test, and Weber provides Kast with the reagents, equipment and sometimes even the funding to create those vaccines in the first place.

“If Martin Kast develops a vaccine, I can do a phase I trial quickly,” Weber says. “I can expedite it; get it into the lab and into patients as quickly as possible. This approach not only speeds up access to innovative ideas, but makes for better trials.”

Kast’s innovative ideas—such as using a unique viral vector called the Venezuelan equine encephalitis replicon to transport mutated cancer genes to patients in the hopes of provoking an immune response to cells containing those genes—would be no more than ideas without the ability to hand them off to clinicians who test the ideas to see if they measure up.

A basic scientist isolated in a laboratory, Weber says, has no contact with the cancer patients in the clinics. “For instance, if Martin needs peripheral blood from patients with cancer, he knows I will get it for him. When he writes a trial, I help him shepherd it through the Institutional Review Board.

“He makes available lab-based expertise that I can take advantage of, and I make available clinical expertise that he can take advantage of—it’s a perfect synergy.” And this kind of creative energy begets more of the same, Weber says. “Martin is a magnet for recruiting other investigators of a like mind.”

As a team, the success of one member benefits the others as well. So when Weber was awarded a grant from the Beckman Foundation to create the Center for Immune Monitoring of Cancer Vaccine Trials, he tapped Kast to head it. “The facility is needed to follow patients in these clinical trials to see if the vaccines I’ve designed induce the desired responses,” Kast says.

Notes Weber: “Our job is to help translate our scientific colleagues’ ideas into clinical trials.” Proximity is one of the keys to facilitating this sort of scientific teamwork, he notes. “When we have a question about how to approach a clinical problem, all we have to do is go across the street,” Weber says. “It makes collaboration easy.”

Group approach

In her search for detectable markers of lung cancer, Ite Laird-Offringa has teamed with specialists from almost every corner of the Health Sciences Campus.

She says she started obtaining archival samples of lung tissue from L.A. County Hospital with the help of two pathology fellows there, Sally Turla, M.D., and Chandrika Seneviratne, M.D., along with Dennis Deapen, Ph.D., executive director of the Los Angeles County Cancer Surveillance Program and Keck School professor of medicine. When it is time to analyze those samples, Michael Koss, M.D., Keck School professor of pathology and medicine, who is an expert in lung cancer, evaluates them and instructs Laird-Offringa’s students in what to look for.

But her list of collaborators does not stop here. Laird-Offringa’s list includes Jeffrey Hagen, M.D., Keck School associate professor of surgery, who helped locate non-cancer lung samples, which, she says, are not easy to come by; Hagen also has a background in statistics, so he was instrumental as an advisor in that arena as well. Kimberly Siegmund, Ph.D., assistant professor in the division of biostatistics at the Keck School, assisted with finding new strategies for analyzing DNA methylation data.

“We also collaborate with my husband’s lab. Peter [Laird, Ph.D., Keck School associate professor of surgery and biochemistry and molecular biology, and director of basic research] developed a technique called MethyLight, which allows us to look for methylation patterns in huge numbers of genes.”

DNA methylation occurs when a methyl group—made of one carbon and three hydrogen atoms—is tacked onto critical stretches of a gene, preventing it from being turned on. But sometimes, methyl groups turn off genes that are supposed to remain unshackled. And that creates problems, since some of these genes may be required to prevent cancer from developing.

“Now that we have found a number of promising markers, we are beginning to look to see if they can be found in blood plasma,” Laird-Offringa says. In that project, she is again working with Hagen and Barbara Gitlitz, M.D., director of the Lung, Head and Neck Program at USC/Norris and Keck School associate professor of medicine, who provides access to patients in various stages of lung cancer.

“Early diagnosis is the key to saving lung cancer patients’ lives,” says Laird-Offringa with grim certainty. “Although we are now able to obtain very detailed images of the lungs, it is still not possible to tell whether observed lesions are cancer. Most are not.”

That is why Laird-Offringa has made it her mission to find ways to take a molecular look into the lungs, non-invasively, to see when and if cancer is beginning to develop and get a head start on curing it.

“It’s all about wanting to make a difference and developing new strategies,” she says. “It’s about wanting to work together.”

Promoting teams

Although the translational research teams have come together in a variety of ways and with a variety of aims, USC/Norris Comprehensive Cancer Center researchers speak as if with one voice about how critical teamwork is when trying to stop cancer.

“A cancer center really can’t exist without promoting translational research,” Weber says. “Other cancer centers do it as well, but USC/Norris is especially good at it. The people here really do get joy out of translation.”

Laird-Offringa agrees: “The tone is set by the people higher up, like [USC/Norris director] Dr. Peter Jones.” She laughs. “We have a cancer center that is run by a Ph.D. That tells you right away that we’re all in it together.”