Possible Treatment Pathway Found for Hard to Treat T-Cell Subtype

Scientists sequencing genomes from 88 tumors diagnosed as anaplastic large cell lymphoma, anaplastic lymphoma kinase negative (ALCL ALK-) have uncovered mutations in two genes that could together be largely responsible for driving the poor prognosis of this disease subtype.

Among non-Hodgkin's lymphoma, T-cell non-Hodgkin's lymphomas represent only about 15 percent of all such diagnoses annually. Among the subtype of T-cell NHLs is anaplastic large cell lymphoma (ALCL). This subtype is further divided into whether the disease is anaplastic lymphoma kinase positive or negative. When positive, the prognosis with treatment is very good. When negative, the prognosis is not good.

This new study, reported in the journal Cancer Cell, might shed some light on why that is the case as well as offer some potential paths for treatment.

The international team of researchers, led by Dr. Giorgio Inghirami of Weill Cornell Medical College and Dr. Raul Rabadan of Columbia University College of Physicians and Surgeons, carried out the genome sequencing of 88 such tumors and determined that 38 percent of them featured the same pair of mutations in genes referred to as JAK1 and STAT3.

Using cell cultures as well as animal models, the team looked at what happened when they left those mutations alone, and when they inhibited them. By inhibiting them, or blocking their activity, they found substantially less tumor growth.

These genes are found on the same cellular signaling pathway. As a consequence, their potential activity in driving tumor growth is greater than if they were on different pathways.

"Since you have two defects, you are pushing the gas much more powerfully than when you push once," said Dr. Inghirami, employing a vehicle metaphor to make his point.

Yet despite this, they are also more vulnerable to effective treatments on account of this as well. According to the researchers, there are drugs available that can inhibit the activity of JAK1, and if you can do that you can also inhibit STAT3 because its activity is contingent on the activity above it, in JAK1.

Since mutations in JAK1 and the harm they can cause are not new to science or medicine, some JAK1 inhibitors already exist for various disorders, and therefore represent possible markers for future treatment of persons diagnosed with ALCL ALK negative.

Source: Cancer Cell