Repurposing Bortezomib

Innovations in Cancer - Summer 2016 - View Full PDF

 Lalitha Nayak, MD

It’s well-known that cancer patients are at increased risk of developing blood clots, both by virtue of the disease itself and because of treatment with antineoplastic agents. Research suggests that people with cancer have between four and seven and a half times the risk of developing a venous thromboembolism, when compared with the general population. Unfortunately, current anticoagulation therapies pose a significant risk of bleeding, all but eliminating them for consideration as a preventive strategy for these patients.

“Among pancreatic cancer patients, for example, almost 40 percent will develop a clot, but we don’t know how to accurately predict the risk,” says Lalitha Nayak, MD Hematologist, UH Seidman Cancer Center and Assistant Professor of Medicine, Case Western Reserve University School of Medicine. “Plus, the risks of anticoagulants are so high in these patients that we can’t justify using them in a preventive way.”

Research in Dr. Nayak’s lab, however, may be changing this calculus. In cell and animal experiments using the cancer drug bortezomib, she and her colleagues have explained why this particular agent decreases the risk of clotting. The biochemistry behind this discovery, she says, could point to a new strategy for anticoagulation, as well as a potential biomarker for predicting clotting risk.

“We’ve known that multiple myeloma patients receiving bortezomib have a dramatically lower risk of clotting,” she says. “This was a very important observation, but people couldn’t explain why. By titrating bortezomib down to very low doses, we’ve found that it has a beautiful anticlotting effect, independent of any decrease in cell numbers. This effect is dependent on the transcription factor Kruppel-like factor 2 (KLF2). Bortezomib increases clotting time by increasing KLF2, without increasing the risk of bleeding.”

Dr. Nayak’s research is funded, in part, by a grant from the National Heart, Lung and Blood Institute to Case Western Reserve University School of Medicine. She and her colleagues have published their findings in the journal Blood.

According to Dr. Nayak, this discovery could have implications not only for cancer patients, but also for the millions of patients with other conditions who are at risk of developing blood clots.

“There are many, many conditions that increase clotting risk, not just cancer,” she says. “Most of these diseases do not have an adequate therapeutic option. At the same time, there are many things that alter thrombosis, but if you don’t understand how it works, it’s hard to take things to clinical trials.

For the first time, we’ve been able to show that this huge effect we’re seeing is due to KLF2. This shows us that KLF2 can be manipulated. Altering KLF2 levels might be a new way to alter the risk for clots. What’s exciting is that bortezomib creates this effect at such low doses, we may not see the side effects we’d normally see.”

Dr. Nayak is currently monitoring KLF2 levels in pancreatic cancer patients to test its potential as a biomarker for clotting risk. She’s also exploring using KLF2 monitoring in patients with antiphospholipid antibody syndrome.

“We’re looking to see what happens to patients’ KLF2 levels over time,” she says. “If we can correlate KLF2 levels with clotting, we might be able to institute anticoagulation therapy with bortezomib at certain quantifiable KLF2 levels. Right now, we wait for patients to clot, and then we treat them. They’re in pain, they already have the clot, and, for cancer patients, we have to hold chemotherapy, which causes a lot of problems. Prevention would be so great. If we could have a drug that decreases the risk for clotting, without altering our bleeding risk, with very low side effects, that would be huge. Bortezomib may be that drug. It may not be an anticancer agent but an anticlotting agent at a very low dose, where it has a totally different effect. That’s where I envision this going.”

For more information on this research, email Dr. Nayak at Lalitha.Nayak@UHhospitals.org.