Novel Molecule Targets Cytokinesis

A compound that blocks cytokinesis by inhibiting TOPK eradicated lung tumors in mice, according to a new study. Researchers now aim to test the compound in clinical trials.

TOPK (T–lymphokine-activated killer cell–originated protein kinase), also known as PBK, is highly expressed in several kinds of tumors, including triple-negative breast cancers and lung cancers. Without the enzyme, dividing cells remain tethered to one another and eventually die, Yusuke Nakamura, MD, PhD, of the University of Chicago, and colleagues reported in 2010, making TOPK a promising target for drug development. Although several cancer drugs disrupt steps in mitosis, no approved drug specifically prevents cytokinesis, which usually caps mitosis.

Nakamura and colleagues' screens for potential TOPK inhibitors first led them to the compound OTS514. The researchers found that it curbed cell growth in 13 of 14 cell lines derived from human cancers. In the one nonresponsive cell line, TOPK was “hardly detectable,” the researchers reported.

To test OTS514′s effectiveness in vivo, Nakamura and colleagues infused the drug into mice that had received transplanted human lung tumors with high TOPK expression. The highest dose of the drug cut tumor growth by 65%, but it also caused severe hematopoietic side effects, such as a drop in white and red blood cells and a surge in platelets.

Seeking to improve upon OTS514, the researchers modified its chemical structure. They produced OTS964, which carries two additional methyl groups. Compared with OTS514, the new inhibitor was less effective at blocking TOPK in vitro, but it was better at destroying tumors in vivo. In 5 of 6 mice with transplanted lung tumors, five injections of OTS964 eliminated the tumors within 2 weeks, the researchers reported last month in Science Translational Medicine. Furthermore, the treatments didn't trigger changes in blood cell counts.

“This was a very rare case in which we observed a complete regression of tumors,” says Nakamura.

The researchers suggest, based on previous reports about other compounds, that one reason for the improved efficacy of OTS964 is that the molecule might remain longer in tumors, giving it more time to kill cancer cells.

“What appeals to me about this study is that they have modified the drug and made a better version,” says Rosemary O'Connor, PhD, of University College Cork in Ireland, who wasn't connected to the research. “It looks reasonably good, but I would be concerned still for the potential for toxicity.”

To test that possibility, the researchers are planning to start phase I trials of OTS964 in summer or early fall of 2015. Because many tumors overexpress TOPK, “we believe this drug can be applied to a wide variety of cancer types,” Nakamura says.