How blood cancer in some can progress as a disease: study

A type of chronic leukemia, or cancer of the blood-forming tissues, can simmer for many years. For a small percentage of patients, the slower-paced disease can turn into an aggressive cancer, called secondary acute myeloid leukemia, which has few effective treatment options. Image for representation. | Photo credit: Getty Images/iStockphoto

Researchers have identified an important transition point in the transition from chronic blood cancer to aggressive blood cancer by conducting experiments in mice, providing a new point of intervention to hinder disease progression, according to a study. study.

Researchers from the Washington University School of Medicine in the United States have shown that blocking a key molecule, called DUSP6, in the transition pathway prevents this dangerous disease progression both in mice with models disease and in mice with tumors taken from human patients. The research appears in the journal NatureCancer.

A type of chronic leukemia, or cancer of the blood-forming tissues, can simmer for many years. Some patients may need treatment to manage this type of blood cancer – called myeloproliferative neoplasms (MPNs) – while others may go through long periods of waiting under watch.

However, for a small percentage of patients, the slower-paced disease can develop into an aggressive cancer, called secondary acute myeloid leukemia, which has few effective treatment options. Little is known about how this transformation takes place.

“Secondary acute myeloid leukemia has a poor prognosis,” said lead author Stephen T. Oh, MD, PhD, associate professor of medicine and co-director of the Division of Hematology in the School of Medicine.

“Almost all patients who develop acute leukemia after a history of myeloproliferative neoplasms will die from the disease. Therefore, one of the main goals of our research is to better understand this conversion from chronic disease to aggressive disease and to to develop better therapies and hopefully prevention strategies for these patients,” Oh said.

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The study suggests that inhibiting this key transition molecule, DUSP6, helps overcome the resistance 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 usually treated with JAK2 inhibitors, but their disease progresses despite this treatment, so we’re also trying to identify how the disease can get worse even under JAK2 inhibition,” Oh said.

Researchers delved into the genetics of these tumors, both during the slow chronic phase and after the disease progressed to an aggressive form while patients were taking JAK2 inhibitors.

The DUSP6 gene stood out as highly expressed in the 40 patients whose tumors were analyzed in this study.

The use of genetic techniques to delete the DUSP6 gene prevented the transition to aggressive disease in mice with models of this cancer.

The researchers also tested a drug compound that inhibits DUSP6 and found that the compound – only available for animal research – halted progression from chronic disease to aggressive disease in two different mouse models of cancer and in mice with human tumors taken from patients.

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Reducing DUSP6 levels both genetically and with drug also reduced inflammation in these models.

Since the drug that inhibits DUSP6 is not available for human clinical trials, Oh and his colleagues want to explore treatments that inhibit another molecule that they believe is activated downstream of DUSP6 and that, according to them, is also necessary to perpetuate the negative effects of DUSP6. There are drugs in clinical trials that inhibit this downstream molecule, known as RSK1.

Oh’s team is interested in studying these drugs for their potential to block the dangerous transition from chronic to aggressive disease and combat resistance to JAK2 inhibition, according to the study. .

“A future clinical trial could enroll patients with myeloproliferative neoplasm who are taking JAK2 inhibitors and still show evidence of their disease getting worse,” Oh said.

“At this point, we could add the type of RSK inhibitor that is currently being tested to their therapy to see if it helps block disease progression to aggressive secondary acute myeloid leukemia.

“A newly developed RKS inhibitor is in phase 1 clinical trials for breast cancer patients, so we hope our work will provide a promising basis for developing a new treatment strategy for breast cancer patients. chronic blood,” Oh said.