Researchers have identified an important transition point in the switch from chronic to aggressive blood cancer by conducting experiments in mice, providing a new point of intervention to hinder the disease’s progress, according to a study.
Researchers at the University of Washington School of Medicine in the US have shown that blocking a key molecule, called DUSP6, in the transition pathway prevents the progression of this dangerous disease in both mouse and mouse models of the disease with tumors sampled from human patients. The research appears in the journal Nature Cancer.
A type of chronic leukemia, or cancer of the body’s blood 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 leukemia, which has few effective treatment options. Little is known about how this transformation occurs.
“Secondary acute myeloid leukemia has a dismal prognosis,” said lead author Stephen T. Oh, MD, PhD, associate professor of medicine and co-director of the School of Medicine’s Division of Hematology.
“Almost all patients who develop acute leukemia after a history of myeloproliferative neoplasms will die of the disease. Therefore, an important 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,” Oh said.
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 that is also used to treat rheumatoid arthritis. “These patients are usually treated with JAK2 inhibitors, but their disease progresses despite this therapy, so we’re also trying to identify how the disease can get worse even in the setting of JAK2 inhibition,” Oh said.
The researchers took a deep dive into the genetics of these tumors, both during the slow chronic phase and after the disease had transformed into the aggressive form while the patients were taking JAK2 inhibitors.
The DUSP6 gene stood out as highly expressed in the 40 patients whose tumors were analyzed in this study.
Using genetic techniques to knock out the DUSP6 gene prevented the transition to aggressive disease in mouse models of this cancer.
The researchers also tested a drug compound that inhibits DUSP6 and found that the compound, available only for animal research, stopped the progression of chronic disease to aggressive disease in two different mouse models of cancer and in mice with human tumors sampled from patients.
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 clinical trials in humans, Oh and his colleagues are interested in exploring treatments that inhibit another molecule that they found to be activated downstream of DUSP6 and that they also showed is required 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 investigating these drugs because of their potential to block the dangerous transition from chronic to aggressive disease and address resistance to JAK2 inhibition, the study said.
“A future clinical trial could enroll patients with myeloproliferative neoplasia who take JAK2 inhibitors and still show evidence of worsening of their disease,” Oh said. “At this point, we could add the type of RSK inhibitor that is now in trials to their trial therapy to see if that helps block the progression of the disease to aggressive secondary acute myeloid leukemia.
“A newly developed RKS inhibitor is in phase 1 clinical trials for breast cancer patients, so we hope that our work will provide a promising basis for developing a new treatment strategy for patients with this blood cancer chronic,” Oh said.
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