T-cell acute lymphoblastic leukaemia (T-ALL) is diagnosed in 90 children and teenagers living in the United Kingdom each year. Most of these patients can expect long-term survival with currently available treatment protocols.

The outcome for patients with recurrent or refractory (drug resistant) T-ALL however is unfavourable and this patient group represents a clinical unmet need.

My research group is based in the Wolfson Childhood Cancer Research Centre (WCCRC) in the Newcastle University Cancer Centre. Our aim is to understand the biology underlying treatment resistant T-lineage haematological malignancies and use this knowledge to improve outcomes for affected children and adults. Our research pertains to T-ALL, T-LBL (lymphoblastic lymphoma) and PTCL (peripheral T cell lymphoma).

The infrastructure at Newcastle University and Great North Children’s Hospital provides a wide range of state-of-the-art services to allow us to interrogate the biology of T-lineage derived malignancies and translate this knowledge into delivering improved therapies in early and late phase clinical trials.

Current research projects at the Wolfson Childhood Cancer Research Centre:

1. Aberrant activation of developmental pathways frequently underlie the development of cancer. Using an shRNA screen against components of the T Cell Receptor (TCR) pathway, we have identified a critical role for the signalling molecule LCK in proliferation of human T-ALL in mouse models. Excitingly, drug resistance in T-ALL cells could be reversed when combining inhibition of LCK with conventional chemotherapy. We are currently working to understand the mechanism underlying the reversal of drug resistance, as well as identify response biomarkers, with the aim to include this novel therapy in early phase trials.
2. The initial phase of clinical treatment for patients with T-ALL consists of a four-drug induction regimen containing dexamethasone, vincristine, asparaginase and daunorubicin (VXLD). Response to this induction treatment, as measured by real-time genomic PCR, is predictive for outcome. Understanding mechanisms that provide resistance against this induction regimen has the potential to improve outcomes. We are currently applying a functional genomic screen, using CRISPR/Cas9 technology, to unravel mechanisms of resistance to VXLD treatment in vitro and in vivo.
3. Philadelphia-like activating kinase mutations are increasingly recognised in B and T-lineage ALL. Patient samples and cell lines carrying ABL1, ABL2, PDGFRA or PDGFRB mutations are subject to extensive characterisation and high throughput screens to establish their prevalence, prognostic impact and identify more efficient therapies.