November 2, 2014
When taken by mouth, the drug was well tolerated with limited toxicity. An intravenous form, delivered within a liposome, was just as effective with fewer side effects. Both approaches — described in the October 22, 2014 issue of Science Translational Medicine — led to complete regression of transplanted tumors.
“We identified the molecular target for this drug ten years ago, but it took us nearly a decade to find an effective way to inhibit it,” said study author Yusuke Nakamura, MD, PhD, professor of medicine at the University of Chicago and deputy director of the University’s Center for Personalized Therapeutics. “We initially screened 300,000 compounds and then synthesized more than 1,000 of them, and found a few that were likely to work in humans. We focused on the most effective. We think we now have something very promising.”
OTS964 targets TOPK (T — lymphokine-activated killer cell — originated protein kinase), a protein that is produced by a wide range of human cancers and is believed to promote tumor growth. High TOPK expression correlates with poor prognosis in patients with breast and lung cancer.
Initial studies of the drug, and a precursor called OTS514, found they were effective in killing cancer cells. But they could disrupt the production of new red and white blood cells, causing hematopoietic toxicity such as mild anemia and increasing the risk of infection. At the same time, the drugs increased the production of platelets, which help in blood clotting.
When the researchers encapsulated the drugs in liposomes — microscopic bubbles similar to a cell membrane, commonly used to transport drugs within the body — the drug no longer caused this decrease in red and white blood cells. This approach “completely eliminated the hematopoietic toxicity,” the researchers wrote.