July 13, 2015
A new compound that locks a disease-related protein
into an inactive position stifled the growth of an aggressive form of leukemia
in laboratory and animal tests, researchers at Dana-Farber Cancer Institute and
other institutions report. When the compound was combined with a steroid, the
leukemia was reduced even further and the animals lived longer than they did
when treated with the compound alone.
The results, published online July 13 by the
journal Cancer Cell, demonstrate that the technique – in which a drug
compound shuts down the protein by snapping it closed, preventing it from
functioning – can be especially effective in some cancers. “Our results were
achieved in an aggressive type of B-cell acute lymphoblastic leukemia [B-ALL], the
most common cancer in children and a highly fatal disease in adults,” said David Weinstock, MD, of Dana-Farber, the
co-senior author of the study with Christoph Gaul, PhD, of Novartis Institute
for Biomedical Research. “But because the same protein is found in an abnormal
form in other cancers, this approach holds promise for treating them as well.”
The study involved a variety of B-ALL in which the
cancer cells carry a rearrangement of the gene CRLF2. (Such
rearrangements occur when DNA damage causes certain genes to be out of their
proper order in a chromosome.) While most children with B-ALL can be
successfully treated, those with this genetic variant often do not fare as
well.
One of the most inviting targets on B-ALL cells
with CRLF2 rearrangements is a signaling protein called JAK2, which the
cells rely on to grow and survive. Drugs that block JAK2 have received Food and
Drug Administration approval for treating diseases such as myeloproliferative
disorders (which affect blood cell growth in the bone marrow) and rheumatoid
arthritis, but they have not been successful in cancer. “While these drugs can
reduce the symptoms associated with certain cancers, they don’t alter the
natural course of the disease,” Weinstock said.
Researchers have shown that such “type I” JAK2
inhibitors fail in cancer because the tumor cells manage to re-route the
chemical signals that usually pass through JAK2. This allows the cells to
resume their hectic growth and division.
In the new study, Weinstock and his colleagues
tested a type II JAK2 inhibitor, which uses a different strategy against the
errant protein. Made by Novartis, the inhibitor, called CHZ868, binds JAK2 into
a tightly clenched position that prevents it from functioning.
Weinstock’s team tested the agent in laboratory
samples of B-ALL with CRLF2 rearrangement, in mice with the disease, and
in mice implanted with human B-ALL tissue. “In each case, we saw good activity:
leukemia cells died, JAK2 signaling was suspended, and survival rates increased,”
Weinstock said. “When we combined CHZ868 with the steroid dexamethasone, the
killing of leukemia cells was much more extensive and the animals lived longer
than they did with CHZ868 alone.”
Especially encouraging was the lack of bone marrow
problems in the treated mice, a possible side effect of JAK2 inhibitors,
Weinstock added.
“JAK2 abnormalities are found in some cases of
triple-negative breast cancer and Hodgkin lymphoma,” he continued. “The success
of CHZ868 in B-ALL suggests that it, or a compound that works by a similar
mechanism, may also be effective in these cancers.”
Funding for the study was provided by the Dana-Farber/Novartis Drug
Discovery Program, the National Cancer Institute (grants R01 CA151898-01 and
T32 CA136432), and the National Heart, Lung, and Blood Institute (grant T32
HL116324).
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