A Novel Use for a Form of Heparin to Treat Neuroblastoma

Researchers at Duke University Health System have identified a new strategy for treating neuroblastoma using a modified version of heparin.

The results of their study of this treatment, which was conducted in mice and human cells, were published in the June 17 issue of the Journal of Clinical Investigation. As reported in the journal, the Duke researchers found that when heparin is altered to remove its blood-thinning properties, it can suppress and shrink neuroblastoma tumors without the threat of severe bleeding.

“Our research translates mechanistic insights about heparin into a potential new therapy for neuroblastoma, and possibly other cancers,” said senior author Gerard C. Blobe, MD, PhD, professor of medicine, pharmacology, and cancer biology at Duke.

Neuroblastoma is typically seen in infants and children. Although neuroblastoma is rare—only 700 new cases are reported in the United States each year, according to the American Cancer Society—it is the most common cancer in infants.

Despite numerous treatment options for neuroblastoma, survival rates in children with advanced cancer are lower than 40% because of disease recurrence and the persistence of residual cancerous cells after chemotherapy. However, one difference between neuroblastoma and other solid tumors is the function of the stroma, or connective tissue around the tumor.

“Most of the time, we think of stroma in solid tumors as a bad thing that helps cancers become more invasive. In neuroblastoma, it’s the opposite: having a lot of connective tissue around the tumor does something favorable for patients,” Blobe said.

Studying the stroma’s biology, the researchers determined that the connective tissue produces and releases receptors involved in nervous system signaling called heparan sulfate proteoglycans. The heparan sulfate proteoglycans had a differentiating effect on the cancer cells that made immature cancer cells act more like mature neurons and prevented them from proliferating.

Heparan sulfate proteoglycans are structurally similar to the anticoagulant heparin, which led the researchers to hypothesize that heparin might recreate the function that naturally occurs in the stroma.

They administered heparin to human neuroblastoma cells in laboratory cultures as well as to mice with neuroblastoma, and found that heparin could differentiate cancer cells and cause tumors to regress in mice.

“Heparin was effective, but caused serious bleeding,” said Erik H. Knelson, an MD/PhD candidate at Duke University School of Medicine and the study’s lead author. “If we could find a modified heparin that still promoted differentiation but did not cause anticoagulation, we might have a successful treatment.”

The researchers studied the structure of heparin and determined that although certain properties were necessary for anticoagulation, only some properties were important for the signaling that promoted differentiation. Using this finding, they identified a derivative of heparin that would allow for differentiation without anticoagulation.

When tested in lab cultures, the heparin derivative suppressed neuroblastoma growth. In mice, it slowed the cancer’s progression, shrunk the tumors, and extended the animals’ lives.

“We want to repurpose a drug that’s already out there for the benefit of patients,” Blobe said. “What’s exciting about this is that there are other tumors in which differentiation is useful, so there’s the potential to apply these insights to other cancers.”

The team is now working to move the research into clinical trials in humans to determine whether the heparin derivative offers the same benefit in humans as it did in mice. Additional funding is needed in advance of further trials; Alex’s Lemonade Stand, a charitable organization, is already helping to translate this into the clinic.

In addition to Blobe and Knelson, study authors include Angela L. Gaviglio of the Department of Pharmacology and Cancer Biology at Duke; Jasmine C. Nee, Mark D. Starr, and Andrew B. Nixon of the Department of Medicine at Duke; and Stephen G. Marcus of Cantex Pharmaceuticals.