HIGHLY EFFECTIVE NEW ANTI CANCER DRUG SHOWS FEW SIDE EFFECTS IN MICE
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.
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