June
15, 2012 in
Cancer A substantial proportion of NK/T-cell lymphomas harbor Janus Kinase 3
gene mutations. Patients with these lymphomas might benefit from treatment with
a Janus Kinase inhibitor according to a study published in Cancer Discovery, a
journal of the American Association for Cancer Research. "Very little was
known about the genetic and molecular defects causing NK/T-cell lymphoma before
we started this work," said Bin Tean Teh, M.D., Ph.D., director of the
National Cancer Center Singapore-Van Andel Research Institute Translational
Research Laboratory at the NCCS, and professor at the Duke-NUS
Graduate Medical
School in Singapore . "There is no
effective treatment and this type of cancer carries an extremely poor
prognosis. "It is tremendously rewarding to have identified genetic
mutations that appear to have an important role in driving the cancer in a
considerable fraction of cases. Moreover, we are excited that there is a drug
already in phase III trials for the treatment of rheumatoid arthritis that
targets the mutant protein. We are in the process of planning a clinical trial
to study whether this drug benefits NK/T-cell lymphoma patients," said
Teh. NK/T-cell lymphoma is a very aggressive form of lymphoma. It is
particularly prevalent in Asia. "Many years ago, I and a colleague came to
the Van Andel Research Institute in Grand Rapids, Mich.," said Teh.
"My colleague unfortunately developed NK/T-cell lymphoma and passed away.
It was the only case of this cancer ever diagnosed in Grand Rapids. As this
illustrates, it is a relatively rare subtype of lymphoma in the United States,
but it is responsible for the deaths of a large number of people in Asia, in
particular in China and Korea. It accounts for almost half of all T-cell
lymphomas in some parts of Asia. "The passing of my colleague, whom I was
very close to, was the reason that I started studying NK/T-cell lymphoma. It
has been a complicated puzzle, but I feel that we have pieced together enough
that we will have an impact on a large number of patients with this
disease." To identify genetic mutations that might have a functional
consequence, Teh and his colleagues sequenced all the genes in NK/T-cell
lymphoma cells from four patients. In addition to mutations in genes known to
be associated with cancer, they detected mutations in the Janus Kinase 3 (JAK3)
gene in the cancer cells from half of the patients. The researchers conducted
follow-up sequencing of NK/T-cell lymphoma cells from an additional 65 patients
and identified JAK3 mutations in 23 of those patients. The mutations enabled
NK/T-cell lymphoma cell lines to grow in culture in the absence of the normally
essential growth factor IL-2. This meant that the mutations caused dysregulated
activation of JAK3, and suggested that JAK3 might be a good drug target. Consistent
with this idea, a JAK inhibitor that is currently being assessed in phase III
clinical trials as a treatment for rheumatoid arthritis killed cultured
NK/T-cell lymphoma cell lines by a process known as apoptosis. "We are
currently putting together a proposal to test JAK inhibitors as a treatment for
NK/T-cell lymphoma with JAK3 mutations," said Teh. "I am hopeful that
we might have found a molecular target for the treatment of a least some
patients with this otherwise fatal disease." Provided by American
Association for Cancer Research
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