A discovery by Van Andel Institute researchers has identified a potential drug target for NK/T-cell lymphoma, a type of cancer responsible for claiming the life of a close friend and fellow researcher.
A study, authored by Bin Tean Teh, M.D., Ph.D., and published this week in Cancer Discovery, a journal of the American Association for Cancer Research, notes that a substantial proportion of NK/T-cell lymphomas harbor Janus Kinase 3 (JAK3) gene mutations, indicating that patients with these lymphomas might benefit from treatment with a Janus Kinase inhibitor.
Lymphoma is a cancer that begins in the immune system. NK/T-cell lymphoma is an aggressive form of the disease with a poor prognosis that is rare in the United States, though prevalent throughout much of Asia. According to Teh, the only case ever recorded in Grand Rapids, Michigan was that which struck close friend and fellow Van Andel Institute researcher, Han-Mo Koo, Ph.D., in 2004.
Teh and Koo began working together at Van Andel Institute in 1999 as a part of a group of founding principal investigators. Koo’s promising work identifying genetic targets for anti-cancer drug development for melanoma and pancreatic cancer was cut short when he passed away from NK/T-cell lymphoma in 2004, at the age of 40. Before Koo died, Teh promised him that he would dedicate his efforts toward finding the genetic basis of the disease.
“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 the disease,” said Teh, 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.
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 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 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.”
Date: June 22, 2012
Source: Van Andel Institute