Cancer Cell Biology, Clinical Trials, DNA damage response and genomic instability
ATM-dependent pathways as therapeutic targets in CLL
The pleiotropic nature of the ATM mutant CLL cellular phenotype provides multiple ways for sensitisation of ATM mutant tumours. This concept is called synthetic lethality. For example, the current hypothesis is that inhibition of DNA repair pathways that cooperate with ATM could sensitize ATM mutant cells by a mechanism that does not involve activation of apoptosis. This lead to the use of a novel, highly specific PARP inhibitor (olaparib) that is already in the phase I/II clinical trials for BRCA mutant tumours in ATM null lymphoid malignancies. The group has shown that ATM null tumour cells show sensitivity to PARP inhibitor both in vitro and in vivo in an ATM null xenograft model. Based on multicentre national collaboration a phase I/II clinical trial with PARP inhibitor in ATM null lymphoid malignancies has been initiated.
Development of murine models for ATM deficient lymphoid malignancies
The mechanisms by which loss of ATM function can promote malignancies at different stages of haematopoietic differentiation are largely unknown. Furthermore, lack of animal models severely hampers the comprehensive development of targeted treatments for these aggressive malignancies. Therefore, an important recent task was to produce an Atm-/- mouse model in which early thymoma development is blocked and the full range of ATM driven haematopoietic malignancies can be recapitulated. To facilitate this task a series of crosses of Atm-/+ heterozygous mice with nude mice lacking a thymus due to loss of the Foxn1 alleles has been undertaken. Atm-/-nu-/- double knockout animals lacking a T cell compartment, display a prolonged median survival time, delayed tumour onset and a change in tumour phenotype towards diffuse large B-cell -like lymphomas (DLBCL) as well as myeloproliferation. This provides an excellent model to study the role of ATM in a wide range of malignancies. Finally, xenografts for all major leukaemias have been developed to facilitate testing of targeted therapies.
Targeting DNA damage response in paediatric ALL
The aim is to design the best strategies of targeting pro-survival pathways that confer apoptosis resistance in ALL. To facilitate this aim the group has undertaken a wide screen of kinome and DNA repair profiles and identified deregulated kinases and DNA repair proteins associated with apoptosis resistance. These proteins will be targeted by pharmacological inhibitors. Leukaemia xenograft models will provide a unique tool to monitor the response of a leukaemia stem cell population in apoptosis resistant leukaemias to any treatment that targets deregulated proteins.
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