Protein that inhibits and reduces the effects of chemotherapy identified

Researchers at Karolinska University Hospital and Karolinska Institutet and their colleagues from Science for Life Laboratories (SciLifeLab) and Heidelberg University have identified a protein that determines the efficacy of cytarabin – the most important drug for treating acute myeloid leukaemia. Their results are published in the scientific journal Nature Medicine.

Some 350,000 people around the world are diagnosed every day with the aggressive form of blood cancer known as acute myeloid leukaemia (AML), only 25 per cent of whom survive beyond the fifth year. Over twenty years ago, survival rates were improved by the use of high doses of the cytotoxin cytarabin, but the efficacy of the drug declines over time in some patients. The mechanism of this resistance has remained something of a mystery; however, in the present study, which involved analyses of 300 patients, the researchers show that a protein called SAMHD1 plays a major part in this by reducing the effect of cytarabin in leukaemia cells, and that leukaemia cells with lower levels of SAMHD1 respond better to the drug. The team was also able to make leukaemia cells more sensitive to cytarabin by blocking the protein.

“Our results go a long way to unlocking the pharmacology of cytarabin in the treatment of leukaemia,” says Nikolas Herold, researcher at Karolinska University Hospital and Karolinska Institutet. “We hope that the results will eventually help to improve the treatment of AML using cytarabin combined with substances that block SAMHD1. More studies will be needed first, however.”

Translational collaboration

Dr Herold is co-lead author of the paper with Dr Sean Rudd. The study was conducted in collaboration with colleagues from Jan-Inge Henter’s and Thomas Helleday’s research groups at Karolinska Institutet and Torsten Schaller’s research group at Heidelberg University, amongst others.

“The results are the product of a successful translational partnership between researchers from Karolinska Institutet, Karolinska University Hospital and SciLifeLlab,” says Dr Herold.

Funding

The study was financed by grants from a number of bodies, including the Swedish Childhood Cancer Foundation, the Swedish Cancer Society, the Swedish Research Council, the Cancer Research Funds of Radiumhemmet, the Knut & Alice Wallenberg Foundation, the Swedish Pain Relief Foundation, the Torsten and Ragnar Söderberg Foundation, the David and Astrid Hagelén Foundation, Stockholm County Council (ALF), the German Research Foundation (DFG) and, in part, the German department of research and education via the Immunoquant project and the HIVERA: EURECA project. S.G.R. is in receipt of an EMBO Long-Term Fellowship. Chemical Biology Consortium Sweden is financed by the Swedish Research Council, Science for Life Laboratories and Karolinska Institutet.

Publication

Targeting SAMHD1 with the Vpx protein to improve cytarabine therapy for hematological malignancies

Nikolas Herold, Sean G Rudd, Linda Ljungblad, Kumar Sanjiv, Ida Hed Myrberg, Cynthia B J Paulin, Yaser Heshmati, Anna Hagenkort, Juliane Kutzner, Brent D G Page, José M Calderón-Montaño, Olga Loseva, Ann-Sofie Jemth, Lorenzo Bulli, Hanna Axelsson, Bianca Tesi, Nicholas C K Valerie, Andreas Höglund, Julia Bladh, Elisée Wiita, Mikael Sundin, Michael Uhlin, Georgios Rassidakis, Mats Heyman, Katja Pokrovskaja Tamm, Ulrika Warpman-Berglund, Julian Walfridsson, Sören Lehmann, Dan Grandér, Thomas Lundbäck, Per Kogner, Jan-Inge Henter, Thomas Helleday & Torsten Schaller

Nature Medicine, published 9 January 2017, doi: 10.1038/nm.4265