June 2, 2016
People with cancer are at increased risk for developing blood clots as DNA, micro-particles and other cellular debris spills from tumor cells into the bloodstream. Many cancer patients also undergo surgery, which increases their risk of clotting even more. But when it comes to lowering the risk for blood clots in patients with cancer, today's doctors face a difficult dilemma.
"When you take cancer patients for surgery, they are at extremely high risk [for clots]," says Rebekah White, an associate professor of surgery at Duke. "But the blood thinners we have available increase the risk of bleeding."
This Catch-22 presents a particular problem for pancreatic cancer patients, who suffer from one of the highest incidence of a condition known as venous thrombosis, in which clots form in large veins. In addition, parts of the clot may break free and travel to lung where they can cause fatal occlusion of the blood supply.
The risk of clots is significant and potentially fatal, but studies haven't shown enough benefit from anti-clotting medications to warrant their routine use in cancer patients not in hospital. Even in the hospital, doctors are often leery of delivering effective blood-thinning medications, fearing that they may cause bleeding complications.
"We can't adequately thin the blood after pancreatic resection," White said. "We need safer anticoagulant medications."
With funding support from the Clinical and Translational Science Awards (CTSA) Programs at Duke and UNC, White, the surgeon, is collaborating with UNC's Nigel Mackman, a distinguished professor of medicine and expert in the study of blood clotting in mouse models. They believe they can find a new and safer approach to anticoagulation by targeting a different part of the blood-clotting pathway.
As Mackman explains, there are two ways to induce a blood clot, referred to as the intrinsic and the extrinsic pathways, that converge on a common pathway. Most anti-clotting drugs work by inhibiting the common pathway but increase bleeding risk. Mackman and White propose that if they could target the intrinsic pathway, they could limit clots with reduced risk of bleeding compared with currently available drugs.
"The intrinsic pathway is not as important for controlling bleeding," Mackman said. "We feel if we can block that pathway, we can come up with a safer approach to prevent clots in cancer patients."
The new Duke-UNC team has three strategies in mind, which they'll soon begin testing in parallel in laboratory mouse models. The first is a method pioneered in the Duke labs of White and Bruce Sullenger, her long-term mentor in the Department of Surgery. It involves a polymer that binds and mops up DNA circulating in the blood stream. The idea is to take away some of the molecular debris that is thought to act as a clot activator in people with cancer.
In the second approach, also championed by White and Sullenger, they'll employ aptamers — artificially engineered antibody-like molecules made of nucleic acids. Aptamers are specifically designed to target particular proteins, such as those involved in clotting. They've already shown promise in reducing clots in clinical trials with patients undergoing coronary interventions.
One of the features that make aptamers particularly appealing is that their effects are quickly reversible with the delivery of an aptamer antidote. "If you were to have a bleeding episode, you could turn it off very rapidly," Mackman says.
In the third and final approach, the researchers will test the use of a novel antibody developed by researchers elsewhere to target a particular clotting factor. "These really are parallel specific aims," White said. "We have all of these reagents available to us now. We're just fine-tuning the [mouse] model and determining the best endpoints."
The researchers expect to begin testing these strategies in the mice within the next month or two.
White and Mackman represent one of four teams to receive collaborative grants from the Duke CTSA and the CTSA at UNC-Chapel Hill this year. These Duke/UNC CTSA Collaborative Pilot Program awards are part of an effort to promote inter-institutional collaborations that can turn basic scientific discoveries into advances in patient care.
UNC and Duke are both members of the Clinical and Translational Awards (CTSA) Program, a national consortium created to improve the way biomedical research is conducted across the country. The CTSA program is funded by the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
Editor's note: This is the fourth and final article in a series exploring four Duke-UNC collaborations funded in 2016 through the Clinical and Translational Science Awards (CTSAs) at Duke and UNC.