Published: Apr. 17, 2012
Updated: Apr. 17, 2012
By Kathleen Yount
Sally Kornbluth, PhD, is a biologist who spends a lot of time thinking about frog eggs. She studies them to understand apoptosis, the cellular death programming that’s present in all normal frog (and human) cells, but becomes disrupted in cancer cells so that they proliferate unchecked.
By “totally pure chance,” she says, she happened to hear about the work of oncologist Neil Spector, MD, a Duke colleague who led the development of the breakthrough breast cancer drug lapatinib (Tykerb) and was looking for new ways to help women who become resistant to the drug.
Kornbluth’s work on apoptosis led the two researchers to a new approach -- they used an existing drug to suppress a protein that regulates tumor resistance, thereby resensitizing the tumors to lapatinib. They hope that someday soon this new treatment method will make its way towards a clinical trial.
This process of aligning bits and pieces of knowledge and ferrying them from a cell culture discovery to a human therapy is called translational research.
Currently the process takes about 15 years -- when it’s successful, that is. That’s not a terribly long time in the realm of science, but time is precious for patients. Speeding up that process -- and making it less a matter of chance than Kornbluth and Spector’s happenstance meeting -- is one of the driving ideas behind Duke’s massive reorganization of its cancer enterprise into the Duke Cancer Institute (DCI).
“Great strides have been made against cancer over the past few decades, but there are still too many people whose cancer cannot be effectively treated,” says Victor J. Dzau, MD, Duke’s chancellor for health affairs, who led the establishment of the DCI in 2010. “It’s clear that we need to accelerate progress against this devastating disease, which is why we created the DCI.”
The unique structure of the DCI represents a more focused, integrated approach to the cancer problem that brings researchers and clinicians together to spark innovation across the spectrum of cancer types, Dzau says.
“Our vision is to transform cancer care by accelerating the translation of research discoveries into breakthrough treatments that improve patients’ experience and outcomes.”
“Traditionally in universities, and in the biomedical industries, there have been excellent basic scientists working in the laboratory, and then there have been excellent physicians working in the clinic,” says Spector, who is co-director of the DCI’s Experimental Therapeutics research program.
Bridging the divides between bench and bedside -- or even among various benches -- is a significant challenge. Yet most cancer experts agree that it’s somewhere between these two worlds where the big advances in oncology will be made.
The Duke Cancer Institute was built to be the bridge.
It all starts with the framework, says Michael B. Kastan, MD, PhD, executive director of the DCI. The institute is designed not around various specialties and disciplines, but around the diseases it seeks to cure.
Like a grid of intersecting interests and skills, there are 10 disease groups for different tumor sites -- each one drawing together clinicians, clinical researchers, and basic scientists -- as well as nine National Cancer Institute-designated research programs focused on crosscutting interests such as radiation oncology, prevention, and cancer genomics.
Since the DCI was created, the disease groups have been meeting on a regular basis -- and creating new connections. “The DCI is juxtaposing people who have common interests, helping people know who their relevant partners are and sparking enthusiasm for new ideas,” says Kornbluth, who is vice dean for basic science in Duke’s medical school.
“For example, [breast oncologist] Kim Blackwell runs clinical trials on lapatinib. She’s a busy clinician; I’m living in a different world. But through interactions with Kim and other clinicians in the breast cancer working group, now I’m thinking, ‘Could we work together?’”
“There is much more communication among faculty, much more thought being given to clinical-trial protocol development in all areas,” Kastan says. “We believe that’s step one toward our goal,” which is essentially to do all phases of drug development under one roof, with fewer costs (both human and capital) and better results.
“New target identification, drug discovery, development, testing, and taking that into clinical trials -- we want to do the whole spectrum within the DCI.”
Paradigm shifts take time. But the DCI’s new way of attacking old challenges makes so much sense, Duke faculty members are embracing the change.
Take Donald McDonnell, PhD. Professor and chair of the Department of Pharmacology & Cancer Biology and a specialist in the development of drugs that target prostate and breast cancers, McDonnell has been at Duke more than 15 years -- but until recently he had minimal interaction with clinicians looking at the other side of what he was looking at.
Now, thanks to the DCI, he’s leading a research project that involves colleagues from his own lab, his department, the university, and the medical center. “We have come together to produce something that’s made me phenomenally reinvigorated,” he says.
Dan George, MD, directs genitourinary medical oncology at Duke. “I’ve been here eight years, and though Donald and I have always had shared interests, we’ve never had the impetus to come together. It was really the DCI umbrella that gave us the priority to do that work.”
For patients with prostate cancer, lowering androgen levels is one of the best available therapies, but a certain percentage of men die from recurring cancer that persists even after inhibiting the production of androgens to nearly undetectable levels.
McDonnell and George explored new ways to explain how these tumor cells survive even when androgen is blocked, and have discovered a potential antitumor molecule that shows promise against these recurring cancers. They’re now in the process of translating their findings into human trials, relying on collaborations with even more groups across the university -- from chemists to imaging specialists.
“It’s been very rejuvenating to feel connected across the institution,” says George. “One great thing about academics is that this environment allows you to do things that you can’t do anywhere else.”
The notion that a closer connection between scientists and clinicians could reap big rewards didn’t fall from the sky, of course. Some Duke teams are living proof.
Nelson Chao, MD, works in stem cell transplantation, an area that he says is, by definition, translational. “This is a fairly new field, so a lot of what we’re doing is cutting-edge,” he says. “Our patients are terribly ill, and we’re always running trials to try to make things better.”
Toward that end, the Adult Blood and Marrow Program he leads formed a cohesive system of constantly going back to the lab to try to find new ways to treat the disease and reduce complications from the treatment. “For us,” he says, “the distance between the laboratory work in mice to humans is relatively short.”
Judging by the leaps made since Duke pioneered the use of cord blood in adult patients in 1996, the system works. Chao’s group conducted the first large study demonstrating success in transplanting stem cells from donors who are not fully matched.
They introduced chemotherapy that is less aggressive than standard practice -- thereby making transplant an option for patients who would otherwise be deemed too sick or too old. New research into hematopoiesis -- understanding what regulates the stem cells that give rise to blood -- is testing new ways to trigger stem-cell renewal. And multiple projects are under way to manipulate transplanted bone marrow to reduce or prevent graft-versus-host disease.
“Really, it’s a remarkable thing that we’re doing,” says Chao. “Nearly all patients can have a stem cell donor.” He credits the success in part to the fact that, in his group, the physicians are also scientists. “It works for what we do. It means the people in the labs understand what the problems really are, so it gives their work more of a focus.”
Chao says he believes the new DCI structure will encourage more groups to strengthen connections to laboratory-based faculty “who can help spin off discoveries to the clinic.” And, he adds, the DCI’s investment in clinical and research resources will lift all boats.
“The work we do is very resource-intensive,” he says. “I think the DCI will bring shared resources that will give us all more security. Having the right people is essential, but so is having the infrastructure.”
The timing of Duke’s investments in cancer research is critical -- it is a necessary adjustment to stay effective in the face of mushrooming numbers of cancer therapies.
Historically, the war on cancer has been a somewhat empiric one, based more on practical experience than on intimate understanding of cancer biology, says Spector.
“Take maximum tolerated dose, which is how most chemotherapies were developed years ago. To kill as many rapidly dividing cells as possible -- knowing that will unavoidably include some normal cells -- you had to set the dose to the limit of what people can stand, and then back down a bit.”
This has changed dramatically, says Kastan, thanks to molecular and cellular biology breakthroughs that have opened windows into the inner workings of malignant cells. From these new discoveries the drug arsenal has changed from one of shock-and-awe to more targeted missiles aimed at different cell processes.
“Over the last 40 years, the problem in cancer was that we’ve had only a handful of drugs we could use, and they were not very specific and they had a lot of toxicities,” Kastan says. “The problem in the next 20 years is going to be the opposite: we’re going to have too many drugs and not know how to use them.”
Indeed, many potentially effective drugs are at our fingertips. But our technologies and tools are outpacing our ability to interpret the information they provide.
“If there’s anything the era of genomics is teaching us, it’s that there’s no such thing as a single tumor type,” Kastan says. “Instead of lung cancer being a disease that’s treated by the typical three or four drugs, we’re going to have 20 subsets of lung cancer, each one treated with different drug combinations depending on its biochemistry and genetics.”
Figuring out those tumor subtypes, and then matching them with the right therapies, is the challenge of the future, he says. The less you know about the mechanism that a drug acts upon, the less you know about how the treatment works and how it will behave in the clinic.
“Then you risk spending five years in clinical trials, coming up with a ho-hum result in patients, and having no information to figure out how to make it better or why it didn’t work,” says Spector. The drug goes on a shelf, collecting dust, when it could quite possibly be effective in a different tumor.
This nearly happened in the case of the new kinase inhibitors for lung cancer, Kastan notes. These drugs are highly effective, but only in a small percentage of patients. “And they almost missed it. The researchers just barely noticed that a small subset of people in the trials were responding, and they eventually figured out that those patients had a specific mutation targeted by the drug. It may only work in 10 percent of lung cancer patients -- but you know, that’s 10 percent.”
To find those needles in the haystack, to actually deliver on the ideas generated by its new collaborative model, the DCI plans to strengthen the pipeline from preclinical testing to clinical research.
“We’re going to have to know much more about the exact setting in which a drug may be useful before we take it into trials in humans,” says Kastan. Toward that end, “We plan to develop better animal model systems of cancer so that we can improve our understanding of the biology of tumors and test these new therapies more efficiently. That way we have lots of information at the outset to tell us how to test the drugs in people -- and in which people.”
Complementing that resource, the DCI is building an enormous data warehouse of tissue samples from tumors biopsied at Duke, so researchers can learn more about the molecular pathology of every type of cancer.
“We need these samples to conduct experiments that will help us understand the potential application of each discovery, and information on patient outcomes to understand how it might be relevant,” says Spector. “Duke is one of only a handful of places in the world with the capability to build a database of this magnitude. The more patients we care for, the larger the database will be, and the greater the impact it will have on the future of cancer research and care.”
DCI leaders have also been working over the past year to strengthen the infrastructure for cancer clinical trials, increasing the involvement of biostatisticians to improve data collection and analysis. “That way,” says Kastan, “we know when we’re finished, we’ll get an answer that will be interpretable -- that we can learn from.”
Clinical trials are what drive discoveries into practice, and the studies are fundamentally intertwined with patient care. The new Duke Cancer Center is designed to encourage patient participation in clinical research by simplifying a complicated process and placing it in a central location.
Because many clinical protocols are multidisciplinary -- with surgical, imaging, chemotherapy, and other components -- having all of those providers on the same site makes participation much easier.
The new building includes dedicated space for clinical trial consultation and coordination, making standard what was previously a rare luxury for clinical trial coordinators -- privacy and quiet space near patient exam rooms to discuss clinical trials, informed consent, and any questions a patient has about clinical research.
“To do great research, we have to bring everyone together -- oncologists, surgeons, biologists, pharmacologists, chemists, radiologists, and the support staff of nurses and coordinators,” says Kastan.
“It takes a village to do this right. And by following this paradigm, when we do clinical trials in patients we will already have learned so much from preclinical testing that we can design trials more effectively. That means it takes fewer patients to have a bigger impact, it costs a lot less money, and we make advances faster.
“At Duke, our goal is not just to take great care of patients. It’s to take great care of them and to cure them,” says Kastan. “You can do that only through research.”