Utrecht, Oss, December, 20th, 2016 – Researchers from the Princess Máxima Center for Pediatric Oncology in Utrecht (The Netherlands) in collaboration with researchers from Erasmus Medical Center in Rotterdam have identified mechanisms underlying resistance to steroid therapy in childhood T-cell acute lymphoblastic leukemia (T-ALL). In the article, which appeared today in the open access online journal PLOS Medicine, new approaches to therapy of childhood T-ALL are proposed based on SynergyFinder™ studies performed at NTRC.
Treatment of childhood leukemia has improved markedly in recent decades, with long-term cure achieved in most patients who have access to modern treatment regimens. However, some patients develop resistance to the steroid drugs which are a key part of combination chemotherapy treatments, which results in poor clinical outcomes. Dr. Jules Meijerink, Principal Investigator at the recently established Princess Máxima Center, studied together with colleagues the causes of resistance by whole genome sequencing on paired samples collected at diagnosis and at remission of thirteen patients. The study was expanded by targeted exome sequencing of candidate genes in samples from 146 additional T-ALL patients. Specific gene mutations in the interleukin 7 (IL7) receptor and its downstream signalling molecules JAK1 and K-RAS were found to associate with steroid resistance and poor clinical outcome. The mutations did not change the functioning of the steroid receptor, but resulted in a strong activation of MEK-ERK and AKT, which are downstream signalling components in the IL7 receptor pathway. To address clinical relevance, primary T-ALL cell samples from eleven patients were analysed in SynergyFinder™ at NTRC. Inhibitors of IL7 receptor signalling, including inhibitors of MEK, AKT and mTOR, synergistically increased steroid-induced leukemic cell death. Discussing the research in an accompanying Perspective article in PLOS Medicine, Drs. Steven Goossens and Peter van Vlierberghe from the Cancer Research Center Ghent (Belgium) conclude that “inhibition of MEK-ERK or PI3K/AKT/mTOR signalling could enhance steroid sensitivity in T-ALL and potentially improve patient treatment outcome, a notion that warrants investigation in future prospective clinical trials.”
To access the article, please follow: http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1002200
NTRC is a precision medicine company dedicated to the development of new anti-cancer drugs. NTRC facilitates the development of novel therapies by providing cancer cell line profiling services (Oncolines™, OncolinesProfiler™, and SynergyFinder™) and target residence time measurements for protein kinases (ResidenceTimer™) on a fee-for-service basis. NFK GreenScreen™, an assay read-out for the cancer immunotherapy drug targets IDO1 and TDO, is supplied to clients globally. For more information please visit www.ntrc.nl or contact [email protected]