new anti-cancer drug shows few side effects in mice

Source:

University of Chicago Medical Center

This is an
illustration depicting liposomal OTS964 entering cancer cells where it
blocks the enzyme TOPK, preventing the final stage of cell division.

Credit: Jae-Hyun Park D.V.M., Ph.D.,
Research Associate/Assistant Professor,
Section of Hematology/Oncology,
The University of Chicago

A new drug, known as OTS964, can eradicate aggressive
human lung cancers transplanted into mice, according to a report in
Science Translational Medicine. The drug, given as a pill or by
injection, inhibits the action of a protein that is overproduced by
several tumor types, including lung and breast, but is rarely expressed
in healthy adult tissues. Without this protein, cancer cells fail to
complete the cell-division process and die.

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.

They tested OTS964 alone and in liposomes in mice with a highly
aggressive human lung tumor known as LU-99. They allowed the tumors to
grow to 150 cubic millimeters -- about the size of a raisin -- and then
administered the drug intravenously to six mice, twice a week for three
weeks. The tumors shrank rapidly and continued to shrink even after
treatment stopped. In five of the six mice, the tumors completely
disappeared -- three within 25 days of the first treatment and two
within 29 days. Mice that received the liposome-coated drug had no
detectable toxicity.

The drug also proved effective when taken in larger doses by mouth.
Six mice with LU-99 lung tumors were fed 100 milligrams per kilogram of
OTS964 every day for two weeks. Again, continuous tumor shrinkage was
observed after the final dose of the drug. In all six mice the tumors
completely regressed. All of the mice had low white-blood-cell counts
after treatment, but they recovered within two weeks.

Although this was a small study, the outcome was dramatic. Seeing
these results was a "quite exciting moment," said Nakamura, who stepped
down from his role as Director in the Japanese Government's Office of
Medical Innovation to join the faculty at the University of Chicago in
April 2012. "It is rare to see complete regression of tumors in a mouse
model," he said. "Many drugs can repress the growth, but it is uncommon
to see them eradicated. This has rarely been reported."

Similar studies of the drug's effects on tumor cells growing outside
the body enabled the researchers to videotape the process as the cancer
cells died. TOPK appears to play a central role late in cytokinesis, the
final stage in cell division. Dividing cancer cells would begin to
separate into two new cells, but were unable to fully disconnect,
retaining an intercellular bridge.

"Without TOPK the cells can't seem to divide; they can't make the
break," Nakamura said. "They can't complete the process. Instead they
remain tethered by a tiny bridge. When that finally breaks apart, they
can't close the membrane. Everything within the cells spills out, they
suffer and then die."

TOPK may provide a good drug target for several types of cancer. This
study involved primarily lung cancers, but the gene is frequently
upregulated in breast, brain, liver, bladder and other solid tumors as
well as certain types of leukemia. The researchers are working with
oncologists at the University to begin a phase-1 clinical trial as soon
as the fall of 2015.

Story Source:

The above story is based on materials provided by University of Chicago Medical Center. Note: Materials may be edited for content and length.

Journal Reference:

1. Yo Matsuo, Jae-Hyun Park, Takashi Miyamoto, Shinji Yamamoto, Shoji Hisada, Houda Alachkar, and Yusuke Nakamura. TOPK inhibitor induces complete tumor regression in xenograft models of human cancer through inhibition of cytokinesis. Science Translational Medicine, October 2014 DOI: 10.1126/scitranslmed.3010277