Two oncologists and a veterinarian walk into a lab. They have a camera, a fluorescent dye, and a four-legged friend. What are they doing?
They’re tackling cancer in humans, of course.
Specifically, they’re testing an imaging device and a protease-activated dye that could revolutionize the way oncologists treat soft tissue sarcoma (STS), a rare type of cancer that can develop in soft tissues such as muscle and nerve tissue of adults and children. Treatment of sarcoma always includes removing the tumor with surgery (or multiple surgeries), and these researchers are developing treatments that may help patients undergo fewer surgeries and less radiation before becoming cancer-free.
But how did they get here? That’s the real story.
The long road a medical innovation takes from concept to implementation is neither quick nor simple. It takes a team of great minds, extensive resources, and great patience to get an innovative treatment to the patients who need it. Often, specific innovations are developed from dealing with general problems, and this one is no different.
The Problem for Patients
According to Brian Brigman, MD, PhD, associate professor of orthopaedic surgery at Duke, the way surgeons and pathologists evaluate whether all of a tumor is removed at the time of surgery hasn’t changed in over 75 years — once the surgeon has resected the tumor, and a margin of normal tissue around it, pathologists paint ink onto the resected tissue, and then slice it up like a loaf of bread. The pathologist and surgeon then examine the specimen to see if any ink is touching tumor.
Even when oncologists believe that they have removed the whole tumor, the cancer recurs locally in about a third of patients. “We call the ‘edges’ of the tumor — those cancerous cells bleeding into the healthy tissue - the ‘margin,’ and even with a microscope, we can only see about one percent of the margin. If we miss the margin during surgery, the patient has a high chance of the tumor recurring,” he says. A recurrence involves more surgeries, more radiation, and more days before becoming cancer-free.
The Small, First Step: Mice
When David Kirsch, MD, PhD, professor of radiation oncology at Duke, began working on mouse models of sarcoma at MIT over a decade ago, he simply wanted to better understand how soft tissue sarcomas develop. Later, he began working on something more specific: using fluorescent dyes to allow surgeons to see the otherwise invisible tumor margin. After coming to Duke, Kirsch joined forces with Brigman to study protease-activated fluorescent imaging agents in sarcomas, meaning the imaging agent is activated in cancerous cells because they secrete more of the protease that turns on the fluorescent dye. A specially-developed imaging device allows surgeons to see the fluorescence in real time, while the patient is on the operating table. Together, the tools may help surgeons detect margins much better than with the naked eye alone. The goal is to help surgeons see and remove the cancerous cells the first time around, preventing recurrences and additional surgeries. Brigman said, “Testing this in the mouse models, we had impressive results – we were able to predict when they would have a local recurrence of sarcoma with better accuracy than pathologists!”
The Next Step: Man’s Best Friend
Once the researchers had satisfactory results in mice, they chose the dye that was giving them the best results, LUM015. The next step was a new study in a population that took them one step closer to human patients: man’s best friend, dogs.
At the time, Will Eward, MD, DVM, assistant professor of orthopaedic surgery at Duke, was one of Brigman’s orthopaedic surgery residents. Conveniently, he is also a veterinarian. Eward was already interested in sarcoma, a form of cancer that behaves and appears exactly the same in dogs as it does in humans, except more quickly. Sarcoma is about 10 percent more common in dogs than it is in humans. Dogs are not typically given radiation, so surgery is often the only treatment. Fortunately for at least nine pets in North Carolina, surgery on tumors is exactly what these doctors wanted to do.
Brigman, Eward, and Kirsch put together a proposal for a grant through the Duke Clinical and Translational Science Award (CTSA) to do similar studies to the mouse model in dogs who have naturally occurring sarcomas.
“The CTSA funding was useful because it helped bridge from testing this kind of technology in mice to the clinical trial in humans by giving us a chance to assess safety in dogs,” said Kirsch. “It also allowed us to do surgeries in dogs with tumors that are much more similar in size to those in humans. So it was an ideal opportunity to test the technology before going into human clinical trials.”
Eward collaborated with Veterinary Specialty Hospital of the Carolinas in Cary, NC, and removed ten tumors from nine dogs, testing the dosage, safety, and effectiveness of the new imaging agent. Working with canine patients also allowed the researchers to gather data about using the imaging device on the surgery table with larger tumors and in dogs who have developed other health concerns over time, the same way that older people do. The change in size of the tumors (and patients) revealed an unexpected issue: during surgery, the dye fluoresced whenever the surgeon used cauterization to seal arteries, something that’s not necessary in the tiny blood vessels of mice. The canine patients also experienced a colorful side effect. “The dye turns urine green for a while - we weren’t expecting that! Fortunately, we discovered these issues with the first canine surgery,” said Eward. “We were able to lower the dosage enough to prevent the cauterization from lighting up too much dye while still showing us the margins effectively.”
The researchers had fantastic results — at nine to fifteen months after surgery, not one dog had a recurrence. After publishing the results of the intervention in dogs in 2013 in Clinical Orthopaedics and Related Research, along with additional pre-toxicity testing, the researchers were ready to move to the most complicated phase yet: human trials.
One Step Closer: The Importance of Volunteers
Clinical trials involving people pose a number of challenges to researchers. Not only must they find funding, resources, and locations to make their research feasible, but they also need volunteers to make research possible.
People are often eager to participate in therapeutic trials — studies designed to treat diseases they have in new ways — but they are often less inclined to participate in studies that aren’t designed to directly affect their personal outcomes. Brigman, Eward, and Kirsch needed to test dosing and safety for the dye in cancer patients before surgeons could start using the imaging device in future patients.
The team needed patients who were willing to participate simply to contribute to the advancement of medicine. Participants in clinical safety trials make real sacrifices: they come in to the clinic a day early for their surgery, or they make an extra trip to the hospital. In return they have only the knowledge that this treatment may help a stranger or friend in the future. Relying on this kind of altruism means that it takes a while to find enough patients — in this case, two years.
Study recruitment is done by the clinical trial research team: the nurses, the people who put together the database, and the infrastructure of the departments supporting the researchers; in this case, the Duke Clinical Research Institute and the Duke Cancer Institute. “The team at Duke is stellar,” Kirsch said, “and it’s thanks to them that we were able to accrue enough patients to get satisfactory data for this probe.”
Fifteen patients over the course of two years agreed to be dosed with the dye and be observed for 24 hours in the Duke Early Phase Clinical Research Unit, a small hospital unit at Duke whose staff are trained to both collect data and ensure the safety of participants in clinical trials.
This trial, the Phase I clinical trial of the probe, lead the researchers to beneficial discoveries and unexpected information. The dye worked best after about four hours in mice, so the researchers expected it to work best when given to humans about 24 hours before surgery. But in the clinical trial, they discovered that wasn’t necessary: the dye only needed about four hours to be most beneficial to human patients.
The Phase I Clinical Trial results were published in January 2016 in Science: Translational Medicine, and the next phase of testing in breast cancer patients is ongoing at Massachusetts General Hospital in Boston. Brigman is submitting an application to the NIH to secure funding for the next phase of sarcoma testing in March.
“I’m looking forward to the next phase of this project,” said Kirsch, “This is the kind of science that has the potential to change lives.”