Bringing Cancer Science to the Bedside

Scientists in the University of Pittsburgh Cancer Institute's molecular and cellular oncology program focus their research on DNA damage and repair and its link to the development and progression of cancer.

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Craig Jordan began studying cancer stem cells in 1998, when it was still a relatively new field. He soon realized that most drug developers weren't taking advantage of this new science, and he started looking into ways to specifically target leukemic stem cells. His big break came when he discovered that the transcription factor, nuclear factor kappa B (NFkB), was overexpressed in the stem cells because there was already a known agent that inhibitted it: parthenolide. "But that was just the beginning," says Jordan. For the next five years he and his team developed and tested analogs of parthenolide that were soluble and would actively kill stem cells. One of the two agents his team found is scheduled to go into Phase I trials this year. "It's a little scary but really exciting," says Jordan. "We won't really know if it works until it goes into humans."

The National Institutes of Health wants this scenario to occur more often. In October 2006, NIH committed $100 million to help build infrastructure for 12 translational (bench-to-bedside) research centers around the country, and pharmaceutical companies are following suit. These programs are looking for qualified scientists to bring onboard. Another major focus of the grant - and an area of opportunity for researchers - is on the training programs that each center is required to develop. Scientists and medical doctors will be able to train quickly on clinical research and regulatory requirements and fill what many translational cancer researchers see as a shortage of well-trained researchers.

The centers won't only focus on cancer research, since NIH wants to increase translational research across all disciplines. However, cancer researchers such as Jordan hope the grant will help make translational work easier by helping to organize and provide the logistic support for clinical trials.

Many academic centers have spent the last few years preparing to increase their translational cancer work, which would shift some of the early work of drug testing from biotech and pharma companies to academic campuses. Such work includes developing and then manufacturing a compound or agent, testing it for toxicity in animals, and then carrying out early clinical trials. For example, the University of Pennsylvania introduced three new core facilities at the Abramson Cancer Center to provide support for translational research: a GMP (good manufacturing practice)-qualified manufacturing facility to produce experimental drugs, a cellular immunology testing facility that processes patient samples and conducts the GLP (good laboratory practice)-qualified assays, and an office that helps researchers prepare the regulation-heavy applications for investigational new drugs. Carl June, head of the program, says he's already found 60 non-cancer researchers at the University of Pennsylvania who are interested in translational work and who will need his center's support.

By 2012, NIH plans to have 60 translational research centers operational. They will act as a consortium, enabling others to share and adopt the best ideas and methods. NIH had planned to give only seven awards the first year, but it was so impressed with the applicants that instead, 12 were granted. They include: Columbia University Health Sciences, Duke University, Mayo Clinic College of Medicine, Oregon Health & Science University, the Rockefeller University, University of California, Davis, UC, San Francisco, University of Pennsylvania, University of Pittsburgh, University of Rochester, University of Texas Health Science Center at Houston, and Yale University.

The new centers will help unite researchers and clinicians, who rarely interact but must do so for translational medicine to work. "Scientists and physicians really live in different worlds and speak different languages. It's difficult to create an environment were scientists and physicians can work effectively," Jordan says. He heads the Wilmot Cancer Center at Rochester, which is constructing a building to house both labs and inpatient facilities so that scientists and physicians can interact on a regular basis. Jonathan Pollett, a postdoc at Pittsburgh, has worked on clinical trials for his doctorate and is trying to improve cancer models. He says working with clinicians is key to his success: "If you don't interact [with physicians] and learn what they need to figure out, it's like building bridges from two ends of a stream and hoping they meet in the middle."

Pharmaceutical companies are also gearing up for more translational medicine. Robert Abraham, vice president of Wyeth's oncology discovery group, says translational medicine is one area that is going to produce "quantum leaps" in drug development, especially in the cancer arena. "Due in large part to the war on cancer for the past 25 years, there's been very intensive effort to dissect the molecular events that lead to cancer development," says Abraham. These advances have led to therapies that target a molecule or oncogenic pathway rather than a cancer subtype. Finding out "who's most likely to respond to the molecularly targeted drugs [across cancer subtypes]," is possible today, says Abraham, with biomarkers that identify patients who will respond to a specific drug.

Wyeth reorganized its translational research efforts in 2006. Gerald Burr, vice president of scientific communications, says that other companies are aggressively recruiting many of the nearly 100 Wyeth scientists who have expertise in translational medicine.

For Preet Chaudhary, the biggest problem in translational research is the lack of qualified personnel. Chaudhary, who directs the center for translational research at Pittsburgh, says he needs people at all levels who understand what is needed to develop a drug for humans, especially the importance of regulatory requirements. When the principal investigator needs to spend too much time explaining the regulatory concerns, Chaudhary says, it can detract from effective management of the trial.

Translational research in cancer is growing. Just in the past five years, Pittsburgh's cancer institute has hired around 51 researchers to do translational work, "each of which brought anywhere from three to 17 people with them," says Clair Collins, assistant director of the news bureau at Pittsburgh's medical center. In general, institutions need more investigators who are trained in both science and medicine and can grasp translational work and drug development, says David Warner, associate director of the Mayo Clinic's NIH-funded translational program. "It's been recognized in the past several years that we're losing our ability to do good quantities of high-quality clinical research," says Warner.

NIH is making it easier for scientists who are interested in translational research but lack the experience. As a requirement for receiving NIH's Clinical and Translational Science Awards, institutions must create formal training and degree programs for its scientists and clinicians to get up to speed on clinical trials. "Institutions will [soon] be providing this type of clinical research education and an expanded menu of options," from full-fledged PhD degrees to an MS for medical doctors and researchers, as well as certificate programs that offer fast-track courses in drug development, says Warner.

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Until now scientists and physicians relied on individual career-development NIH grants that allow them to take time off their degrees to learn about clinical research. Jennifer Grandis, an otolaryngologist at the University of Pittsburgh, took a year off towards the end of her residency to do research in a molecular biologist's lab at the cancer center. "After I became competent in doing the surgery, I thought, 'this isn't enough,'" she says. "I wanted to understand how to prevent these tumors." She sees patients one day per week and does surgery one day per week, but the rest of her time is devoted to clinical research. She expects to start a Phase I trial of a new compound later this year.

"[These degrees are] going to be the future," says Paul LaCelle at Rochester University. "A PhD in genetics [alone] won't be all that sought after." The master's program at Rochester is starting small, taking four graduate students per year and two PhD students. They expect the PhD program will be approved this summer.

Chaudhary hopes to retain in his own labs some of the students trained through Pittsburgh's programs. He says he looks forward to working with excellent cancer researchers who are well versed in the intricacies of clinical trial protocols.

Some scientists say they shy away from translational cancer work, fearing they'll get lost in the crowd of investigators needed to bring a drug to the clinic. Researchers typically measure their progress by the number of publications to their name, but clinical trials often take more time to plan and execute than other projects, which limits the number of studies in which scientists can participate. And with many coauthors, individual scientists share a smaller slice of "glory pie" when involved in a set of significant findings. "There has been a lot of resistance by researchers to shift resources from basic [science] to do clinical science," says Francesco Marincola, editor in chief of the Journal of Translational Medicine. Warner expects that to change when translational research is made into a distinct academic discipline through the specialized degree programs.

Some institutions aren't waiting for the reputation of these programs to trickle down. At the Abramson Cancer Center, June says many at his institute are starting to think about how to promote clinical researchers who will have fewer publications to show for their efforts. "It's a national issue," he says. "We're going to have to learn how to promote people like this. [Translational research] is a new specialty."