Researchers have identified an important transition point in the shift from chronic to aggressive blood cancer by conducting experiments in mice, which the study says provides a new point of intervention to slow the progression of the disease.
Scientists at Washington University School of Medicine in the US have shown that blocking a key molecule called DUSP6 in the transition pathway prevents this dangerous progression of the disease both in mice with disease models and in mice with tumors taken from human patients. The research appears in the journal Nature Cancer.
A type of chronic leukemia, or cancer of the blood-forming tissues in the body, 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, in 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. Little was known about how this transformation takes place.
“Secondary acute myeloid leukemia has a bleak prognosis Almost every patient who develops acute leukemia with a history of myeloproliferative neoplasms will die from the disease. Therefore, the main goal of our research is to better understand this transition from chronic to aggressive disease and to develop better therapies and hopefully prevention strategies for these patients” said lead author Stephen T. Oh, MD, PhD, associate professor of medicine and co-director of the Division of Hematology at the School of Medicine.
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. The researchers took a deep dive into the genetics of these tumors, both during the slow chronic phase and after the disease transformed into an aggressive form when patients took JAK2 inhibitors. The DUSP6 gene stood out as highly expressed in 40 patients whose tumors were analyzed in this study.
Using genetic techniques to remove 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 – halted the progression of chronic disease to aggressive disease in two different mouse models of cancer and in mice with human tumors taken from patients.
Reducing DUSP6 levels both genetically and by drug also reduced inflammation in these models. Since a 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 they found to be activated downstream of DUSP6, which according to them also required to maintain 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 exploring these drugs for their potential to block the dangerous transition from chronic to aggressive disease and address resistance to JAK2 inhibition, the study said.
Oh says “At that point, we could add the type of RSK inhibitor that’s now in trials to their therapy to see if that helps block disease progression to aggressive secondary acute myeloid leukemia. The 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 patients with this chronic blood cancer”.
by: Vaishali Verma
