New cheap drug targets therapy resistance in acute myeloid leukaemia
A common and inexpensive drug can be used to counteract treatment resistance in acute myeloid leukemia (AML), one of the most common blood cancer forms in adults, according to a study led by researchers from SciLifeLab and Karolinska Institutet. The study was published in the medical journal EMBO Molecular Medicine and the researchers will now launch a clinical study where a combination of drugs will be tested.
Every year, around 350 people from Sweden are diagnosed with AML and only one in four survives. Mortality is especially high in older patients. So far, one of the most common drugs used to treat AML is cytarabine (ara-C), a cytotoxic drug that disrupts cell growth. The problem, however, is that many patients respond poorly to the treatment due to high levels of SAMHD1, which can break down the active substance in cytarabine ,ara-CTP.
Patients with high levels of SAMHD1 have a much lower survival rate when treated with cytarabine, suggesting that a way to inhibit the effects of the enzyme could be a promising strategy to improve existing AML treatments.
In the study, co-led by first author Sean Rudd (SciLifeLab/Thomas Helleday’s group/Karolinska Institutet) and last author Nikolas Herold (Karolinska Institutet), the researchers tested more than 33,000 different substances and identified three, belonging to a group called ribonucleotide reductase inhibitors (RNRi), that could reduce SAMHD1’s ability to deactivate ara-CTP: hydroxyurea, gemcitabine and triapine. The screening was performed at the SciLifeLab Chemical Biology Consortium Sweden (CBCS).
“Supplementation of each of these three substances significantly enhanced the efficacy of cytarabine treatment in high SAMHD1 cell samples. We could see this in cell samples from both adults and children. In AML mice, we were also able to show a significantly prolonged average survival rate when cytarabine was combined with an RNR inhibitor” said Nikolas Herold, in a press release from Karolinska Institutet.
All three substances have previously been used or tested when treating various forms of cancer but so far they have not been systematically tested in combination with cytarabine. The combination treatment in mice did not show any adverse side effects beyond those already known with cytarabine alone.
A clinical study is now planned to evaluate the effects of combining cytarabine and hydroxyurea in newly diagnosed patients. The study is done in collaboration with the Swedish AML group and starts recruiting patients within a few weeks.
“Hydroxyurea is a proven drug that is already used to treat AML so we believe it has great potential. Should it prove that our research results work even in clinical use, the treatment of AML could be improved even in developing countries with limited resources because hydroxyurea is patent-free and does not cost more than ibuprofen” says Nikolas Herold.
The researchers were also able to show how the RNR inhibitors affected SAMHD1 levels purely mechanistically.