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US scientists identify molecule that triggers aggressive blood cancer

Scientists at Washington University School of Medicine in St. Louis said that they identified an important transition point in the shift from chronic to aggressive blood cancers, called secondary acute myeloid leukaemia (sAML), that is seen in some patients.

The findings of the study, published recently in the journal Nature Cancer, researchers said that blocking a key molecule in the transition pathway prevents this dangerous disease progression in mice with models of the disease and in mice with tumours sampled from human patients.

“Secondary acute myeloid leukaemia has a grim prognosis,” said the senior author of the study, Dr Stephen T. Oh, an associate professor of medicine and co-director of the Division of Haematology at the School of Medicine.

Pointing out that almost every patient who develops acute leukaemia after a history of myeloproliferative neoplasms will die from the disease, Dr Oh added, “Therefore, a major focus of our research is to better understand this conversion from chronic to aggressive disease and to develop better therapies and, hopefully, prevention strategies for these patients.”

Inhibiting a key transition molecule, called DUSP6, helps to overcome the resistance that these cancers often develop to JAK2 inhibitors, an anti-inflammatory therapy also used to treat rheumatoid arthritis, which is typically used to treat these cancers, the researchers said.

“These patients are commonly treated with JAK2 inhibitors, but their disease progresses despite that therapy, so we are also trying to identify how the disease is able to worsen even in the setting of JAK2 inhibition,” said Oh, who treats patients at Siteman Cancer Centre at Barnes-Jewish Hospital and Washington University School of Medicine.

To understand the phenomenon, the researchers conducted a deep dive into the genetics of these tumours, both during the slow chronic phase and after the disease had transformed into the aggressive form while patients were taking JAK2 inhibitors and found that in 40 patients, whose tumours were analysed, the DUSP6 gene stood out as highly expressed.

However, when scientists employed genetic methods to eliminate the DUSP6 gene in mouse models, they discovered that the development of sAML was halted.

The researchers also tested a drug compound that inhibits DUSP6 and found that it stopped the progression of the chronic disease to the aggressive disease in two different mouse models of cancer and in mice with human tumours sampled from patients.

According to researchers, in these models, decreasing DUSP6 levels genetically and medicinally also lowered inflammation.

Since the drug that inhibits DUSP6 is not available for human clinical trials, Dr Oh and his colleagues are interested in exploring treatments that inhibit another molecule that they found is activated downstream of DUSP6 and that they showed also required to perpetuate the negative effects of DUSP6.

There are drugs in clinical trials that inhibit this downstream molecule, known as RSK1. Dr Oh’s team is interested In examining these medications' ability to prevent the harmful shift from chronic to aggressive disease and address resistance to JAK2 inhibition.

“A future clinical trial might enrol myeloproliferative neoplasm patients who are taking JAK2 inhibitors and, despite that, show evidence of their disease worsening,” Dr Oh said.

“At that point, we might add the type of RSK inhibitor that is now in trials to their therapy to see if that helps block the progression of the disease into an aggressive secondary acute myeloid leukaemia,” he added.

“A newly developed RKS inhibitor is in phase 1 clinical trials for patients with breast cancer, so we are hopeful our work provides a promising foundation for developing a new treatment strategy for patients with this chronic blood cancer,” he further added.

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