Investigators say they have uncovered a new approach for treating ALK-negative anaplastic large cell lymphoma (ALCL).
Results of genomic analyses indicated that many cases of ALK-negative ALCL may be driven by alterations in the JAK/STAT3 pathway, and in vivo
experiments showed the disease can be inhibited by compounds that target this pathway.
The investigators believe these compounds could be more effective than current therapies.
“Current therapies for this form of lymphoma fail to work in the majority of cases,” said Raul Rabadan, PhD, of Columbia University in New York, New York.
“However, now that we know the mutations that drive a significant percentage of cases, we can envision a new, personalized genomic approach to the treatment of ALK-negative ALCL.”
Dr Rabadan and his colleagues recounted their discovery of the mutations in Cancer Cell.
The team had sequenced the exomes and RNA of cancer cells from 155 patients with ALCL and 74 control subjects with other types of lymphoma.
Results revealed mutations in either JAK1 or STAT3 in about 20% of the 88 patients with ALK-negative ALCL. Of that 20%, 38% had mutations in both genes.
The investigators also detected the presence of several novel gene fusions (NFκB2-ROS1, NFκB2-TYK2, NCOC2-ROS1, and PABPC4-TYK2), some of which appear to activate the JAK/STAT3 pathway (NFκB2-ROS1 and NFκB2-TYK2).
Patients with these fusions did not have JAK1 or STAT3 mutations, which suggests the fusions are an independent cause of ALK-negative ALCL.
To confirm whether JAK1 and STAT3 mutations can cause ALK-negative ALCL, the investigators induced these mutations in normal human cells. The mutations did, in fact, lead to diseased cells.
Finally, the team tested JAK/STAT3 pathway inhibitors—ruxolitinib and PUH71—in mouse models of ALK-negative ALCL. And they found that both drugs significantly inhibited tumor growth.
“Our findings demonstrate that drugs targeting the JAK/STAT3 pathway offer a viable therapeutic strategy in a subset of patients with ALCL,” Dr Rabadan said.
“A couple of JAK/STAT3 inhibitors have been approved by the FDA for the treatment of psoriasis and rheumatoid arthritis, and several more are currently in clinical trials. These could be tested in patients whose genetic profile matches those we identified in our study.”
