Children’s Cancer Group led by Professor Vaskar Saha
The Children’s Cancer Group is investigating the biological mechanisms of therapeutic failure in childhood acute lymphoblastic leukaemia (ALL). ALL is a fast growing cancer of the white blood cells. Lymphocytes are a type of white blood cells that help the body to fight infections. In ALL, the body produces vast amounts of abnormal precursors of lymphocytes, so called lymphoblasts. These blasts are unfunctional and overcrowd the bone marrow, so there is not enough space for other blood cells such as red blood cells and platelets.
The group conducts international Phase II and III trials in high risk childhood ALL. The ALLR3 international trial in relapsed childhood ALL has improved outcome in this group of children by 10 % over that achieved in the previous decade. The trials demonstrated that the hitherto rarely used drug Mitoxantrone was superior to the previously used drug Idarubicin and that minimal residual disease (MRD) is not a suitable surrogate marker of outcome. The therapeutic strategy has been adopted worldwide and will form the backbone of the new international relapsed trial, IntReALL, which will open in 20 countries. Another pan-European collaboration, EsPhALL, has demonstrated the benefit of Imatinib in children with Philadelphia positive ALL. This trial has now been replaced by CA180-372 which is examining the role of Dasatinib in Philadelphia positive ALL. A large international collaborative study has also identified strategies for patients with refractory disease. Currently in development is a simplified strategy for children with ALL in countries with fewer resources, called ICiCle.
To investigate the biological basis for therapeutic failure, gene expression profiling (GEP) was used to characterise a new high-risk cytogenetic subtype designated as iAMP21. GEP identified the overexpression of the lysosomal cysteine protease asparginyl endopeptidase (AEP) in high-risk cytogenetic subtypes and it was discovered that leukaemic proteases inactivate the key anti-leukaemic drug L-Asparaginase . The group used this information to design new and more potent asparaginase molecules, work which has led to the first nationwide biomarker and pharmacokinetics study in childhood ALL. Next, a proteomic discovery approach was used to identify mechanisms by which disease recurrences occur within the central nervous system (CNS), which showed that cells transgress the blood brain barrier via diapedesis. The in vitro and in vivo systems developed are now being used to test the efficacy of novel targeted compounds. Investigations of the Children’s Cancer Group suggest that the host-tumour interactions play a key part in the response to therapy and the current focus of interest is in the leukaemic microenvironment.
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The Children’s Cancer Group is part of the Institute of Cancer Sciences within the Faculty of Medical and Human Sciences at The University of Manchester. Find out more about the work of the Children’s Cancer Group.