My team and I investigate childhood leukaemia, the cause of more deaths than any other malignancy in children. Our research into this disease is driven by challenges observed in the clinic. We integrate these observations with translational research efforts with the aim to develop novel therapies.
The current project aims to identify candidate drugs, approved for clinical use, that have unanticipated, or "off target" anti-leukaemia properties. This process is called drug repositioning. The potential and cost-effectiveness of this approach offers real hope for the discovery of novel anti-cancer therapies.
Leukaemia is a cancer of the blood forming cells. Major progress has been made in the treatment of this disease. However, drugs that have been developed to treat leukaemia still fail in about half the patients with Acute Myeloid Leukaemia (AML). New treatments are urgently needed. To discover new treatments we need to understand how normal blood cells are rewired to become leukemic.
Much of the work in the group has focussed on rearrangements of the MLL gene. 1 in 5 children with AML have rearranged the MLL gene, making it the most common genetic mutation identified in AML. A few years ago, we showed that this rearrangement is key in the establishment and maintenance of the transformed phenotype. Next we took on the challenge to identify which pathways are selectively important in the establishment and maintenance of the MLL rearranged transformed phenotype and will therefore act as novel therapeutic targets for cancer treatment. We employed functional genomics approaches to discover that an alternative stem cell pathway, called the non-canonical Wnt pathway, was activated in leukaemia. Inhibition of this pathway blocked the leukaemia and will offer a possible cure for this disease.
Discoveries made during our Pathway Discovery provide clinical relevant targets for new medicines. However, developing a brand-new drug takes an enormous amount of time. To translate promising targets into approved drugs often takes more than 15 years. It is crucial to advance strategies to reduce this time frame, decrease costs and improve success rates.
Drugs usually bind to multiple protein targets or even unintended off-targets. Such drug promiscuity has often led to unwanted or unexplained drug reactions, resulting in side effects of treatments. However, in some cases, these unintended targets are a potential cure for another disease. These drugs are already approved for other uses in humans, so detailed information about them are available. Because of this, repositioned candidate therapies could be ready for clinical trials quickly. Therefore, we established a Drug Discovery pipeline for identifying drugs that could inhibit the pathways identified in our Pathway Discovery.
One child lost to leukaemia is one too many. Everything we do is built around the need for better treatments to improve outcomes for children with leukaemia and give these children a chance for a better life. To fight this terrible disease; we apply cutting-edge discovery research such as whole transcriptome RNA sequencing and high-throughput cellular assays. We use bioinformatics on our generated data to decipher the aberrant biological networks activated in leukaemia. This is combined with mapping of these aberrant networks to corresponding patterns produced by drug candidates. These data are validated through functional experiments in our laboratories. For each step taken in the laboratory we ask: how will this help towards a novel therapy? Never forgetting our ultimate goal: To find a cure for every child with leukaemia.
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