Context

• The researchers at Washington University School of Medicine, US, have shown that blocking a key molecule, called DUSP6, in the transition pathway prevents this dangerous disease progression both, in mice with models of the disease and in mice with tumours sampled from human patients.

• Researchers have identified an important transition point in the shift from chronic to aggressive blood cancer by conducting experiments in mice, providing a new intervention point for hampering the progress of the disease.

Key Findings

• A type of chronic leukaemia, or cancer of the body’s blood-forming tissues, can simmer for many years. Some patients may need treatment to manage this type of blood cancer – called myeloproliferative neoplasms (MPN) – while others may go through long periods of watchful waiting.

  

• However, for a small percentage of patients, the slower paced disease can transform into an aggressive cancer, called secondary acute myeloid leukaemia, that has few effective treatment options.
  • Little has been known about how this transformation takes place.
• Secondary acute myeloid leukaemia has a grim prognosis.
• The study suggests that inhibiting this key transition molecule, DUSP6, helps overcome the resistance that these cancers often develop to JAK2 inhibitors, the therapy typically used to treat them.
• JAK2 inhibitors are an anti-inflammatory therapy also used to treat rheumatoid arthritis.
• These patients are commonly treated with JAK2 inhibitors, but their disease progresses despite that therapy, so we’re also trying to identify how the disease is able to worsen even in the setting of JAK2 inhibition.
• 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.
• The DUSP6 gene stood out as highly expressed in the 40 patients whose tumours were analysed in this study.
• Using genetic techniques to delete the DUSP6 gene prevented the transition to aggressive disease in mice with models of this cancer.
• Reducing DUSP6 levels both genetically and with a drug also reduced inflammation in these models.
• Since the drug that inhibits DUSP6 is not available for human clinical trials, the researchers are interested in exploring treatments that inhibit another molecule that they found is activated downstream of DUSP6 and that they showed is also required to perpetuate the negative effects of DUSP6. There are drugs in clinical trials that inhibit this downstream molecule, known as RSK1.

Source: TH

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