According to a study, scientists have used mouse trials to identify a crucial turning point in the progression of blood cancer from chronic to aggressive, offering a fresh opportunity for intervention to halt the disease's progression.
Researchers from Washington University School of Medicine in the US have demonstrated that blocking DUSP6, a crucial molecule in the transition pathway, stops the fatal disease from progressing in both mouse models of the condition and mice with tumours taken from human patients. The study has been published in the journal Nature Cancer.
A particular type of chronic leukaemia, or cancer of the tissues that produce blood, can develop over a long period of time. Myeloproliferative neoplasms (MPN) are a form of blood cancer that can be managed by some individuals with treatment and long periods of watchful waiting for others.
However, in a tiny number of people, the slower-moving illness might develop into secondary acute myeloid leukaemia, an aggressive cancer with limited curative therapies. About how this change occurs, little is known.
Senior author Stephen T. Oh, MD, PhD, an associate professor of medicine and co-director of the Division of Hematology at the School of Medicine, said, "Secondary acute myeloid leukaemia has a terrible prognosis."
Nearly all patients with acute leukaemia who have a history of myeloproliferative neoplasms pass away from the illness. To better understand this transition from a chronic to an aggressive disease, as well as to create better treatments and, ideally, preventative measures for these individuals, is a significant goal of our research, said Oh.
According to the study, blocking the crucial transition molecule DUSP6 aids in overcoming the resistance that these tumours frequently develop to the medicine that is generally used to treat them, JAK2 inhibitors.
Anti-inflammatory JAK2 inhibitors are also used to treat rheumatoid arthritis.
Despite the fact that JAK2 inhibitors are frequently used to treat these individuals, Oh said, "we're also trying to identify how the disease is able to worsen even in the setting of JAK2 inhibition."
While patients were receiving JAK2 inhibitors, the researchers looked closely at the genetics of these tumours both during the sluggish chronic phase and after the disease had progressed to the aggressive type.
In the 40 patients whose tumours were examined in this study, the DUSP6 gene stood out as being highly expressed.
In mice with cancer model, genetic methods to remove the DUSP6 gene inhibited the onset of aggressive disease.
The researchers also tested a drug compound that inhibits DUSP6 and discovered that it prevented 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. However, the compound is only available for animal research.
Inflammation was decreased in these models by both genetically and pharmaceutically lowering DUSP6 levels.
Oh and his colleagues are interested in investigating treatments that inhibit a different molecule that they discovered is activated downstream of DUSP6 and that they showed is also necessary to sustain the negative effects of DUSP6 because the drug that inhibits DUSP6 is not yet available for human clinical trials. Clinical trials are now being conducted on medications that block RSK1, a downstream molecule.
According to the study, Oh's team is interested in examining these medications for their ability to prevent the risky shift from a chronic to an aggressive disease and address JAK2 inhibition resistance.
Myeloproliferative neoplasm patients who are on JAK2 inhibitors yet exhibit symptoms of their condition getting worse may be included in a clinical trial in the future, according to Oh.
At that point, we may supplement their current treatment with an RSK inhibitor to determine if it can prevent the development of an aggressive secondary acute myeloid leukaemia.
According to Oh, "We're hopeful that our work provides a potential foundation for creating a novel therapy strategy for individuals with this chronic blood cancer." A recently produced RKS inhibitor is currently undergoing phase 1 clinical trials for patients with breast cancer.
You must be logged in to post a comment.