07 October 2016
A “promising” new approach to developing new therapies for acute myeloid leukaemia has been unveiled by an American research team.
The research team, which was led by Massachusetts General Hospital (MGH) and the Harvard Stem Cell Institute, has identified a crucial dysfunction in blood cell development underlying the disease.
Writing in Cell, they say that inhibiting the action of a specific enzyme prompts the differentiation of leukaemic cells, reducing their number and decreasing their ability to propagate the cancer.
Senior author Dr David Scadden, director of the MGH Center for Regenerative Medicine (MGH-CRM) and co-director of the Harvard Stem Cell Institute (HSCI), said new therapies for AML, which has a 30% five-year survival rate, are extremely limited.
“We are still using the protocols developed back in the 1970s, so we desperately need to find new treatments,” he said.
Although a wide range of genetic changes occurs in AML, the research team undertook the research in the belief that the effects on differentiation had to travel through a few shared molecular events.
Using a method created by lead author Dr David Sykes, of the MGH-CRM and HSCI, the team discovered that a single dysfunctional point in the pathway common to most forms of AML could be a treatment target.
Previous studies had shown that the expression of a transcription factor called HoxA9 is maintained in 70% AML patients. Because no inhibitors of HoxA9 had been identified, the research team based the screening of potential inhibitors based on if they could overcome the differentiation blockade characteristic of AML cells.
A cellular model of AML was set up that induced HoxA9 overexpression in mouse myeloid cells, which were genetically engineered to glow green if they reached maturity.
The team screened more than 330,000 small molecules to find which would produce the green signal in the cells, indicating that the HoxA9-induced differentiation blockade had been overcome.
This resulted in just 12 compounds producing the desired result. Eleven of these suppressed a metabolic enzyme called DHODH, which was not previously known to have a role in myeloid differentiation.
Further tests showed that DHODH inhibition induced differentiation in both mouse and human AML cells.
When they tested a known DHODH inhibitor in several mouse models of AML, they found a dosing schedule that reduced levels of leukemic cells and prolonged survival.
Treatment for up to 10 weeks appears to have led to long-term remission, including a reduction of the leukaemia stem cells that can lead to relapse.
Additional investigation of the mechanism underlying DHODH inhibition should allow development of protocols for human clinical trials, added Dr Scadden.
Inhibition of Dihydroorotate Dehydrogenase Overcomes Differentiation Blockade in Acute Myeloid Leukemia Cell 15 September 2016
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