Cardiff Haematology Acute Myeloid Leukaemia Research Unit

Research

Cardiff AML Target Discovery and Translation Research Group

This group is co-led by Professors Alex Tonks and Richard Darley.

Together with our clinical colleague (Dr Steve Knapper) we form a team of experienced scientists and clinicians with a track record centred on integrating fundamental research on haematopoietic development and leukaemia with translational and preclinical studies aimed at drug targeting of molecular abnormalities.

Our translational pipeline is aimed at delivering new therapeutic approaches for the treatment of resistant disease in AML involving the identification (proteomics / genomics / metabolomics) and mechanistic evaluation (knock-in / knock-out) of novel abnormalities in this disease as well as the development of preclinical models for testing of targeted therapies.

Current targets under investigation are NOX oxidases, carbohydrate metabolism (PFKFB3), hnRNP, CD200 and the S100 family of calcium binding proteins and novel factors regulating β-catenin translocation.

AML Microenvironment Group

The AML microenvironment group is part of the Cardiff Experimental Cancer Medicine Centre (ECMC) and is co-led by Dr Joanna Zabkiewicz and Dr Caroline Alvares. Our  principal focus is the  pre-clinical development of novel therapeutics that are active against primary leukaemia cells which have been demographically, cytogenetically and molecularly characterised with clinical outcome data.

Current research in the group has identified a key role for the bone marrow microenvironment in drug resistance and relapse in AML. Bone marrow support cells called mesenchymal stem cells (MSCs) help to provide structure for haematopoietic stem cells to grow and our research is investigating how abnormalities in a patient’s microenvironment may make some patients resistant to therapy, unable to support normal donor stem cell growth and suppress anti-leukaemic immune cells.

We have recently developed several co-culture models of the bone marrow microenvironment in which we can study cell-to-cell behaviours such as adhesion, cell growth, immunosuppression and response to therapy. Through these models the group aims to stratify subgroups of patients that may benefit from targeted therapies and to characterize co-operative signalling events underpinning drug resistance, critical for designing therationale for novel microenvironment-based therapy combinations in the clinic.

Clinical Development Group

In addition to working closely with the above groups, Dr Steven Knapper leads the Clinical Development Group which aims to develop novel target therapeutic agents in AML (and other myeloid malignancies) through to early phase clinical studies.

Dr Knapper is a clinical academic haematologist based at the University Hospital of Wales, Cardiff and is also a member of the Cardiff AML Target discovery and translation research group. Dr Knapper has coordinated ‘back to bench’ correlative pharmacodynamic studies of target agents within international clinical trials (mTOR and FLT3 inhibition in the AML15 and 17 studies, pharmacokinetics of arsenic in AML17).

He is currently involved in the development of clinical research at a national level through membership of the UK NCRI AML and Myeloproliferative Neoplasms Clinical Study Groups and he leads Cardiff’s Bloodwise Trials Acceleration Programme (TAP). Recently, the actions of the monocyte-targeted histone deacetylase inhibitor Tefinostat have been characterised in AML and chronic myelomonocytic leukaemia (CMML).

Dr Caroline Alvares is a Clinical Senior Lecturer in Haematology at Cardiff University. She has a background PhD in working with primary AML cells in stromal co-culture systems and a research interest in the AML microenvironment. She is also a principal investigator and co-investigator on phase I, II & III studies in AML at the University Hospital of Wales and has a special interest in clonal haematopoiesis in the general population preceding the onset of MDS and AML.

Also see clinical trial activity in ‘projects’ tab.

AML Clinical Trials Molecular Group

The portfolio of the group is led and co-ordinated by Amanda Gilkes. The group provides ECMC-supported real time molecular screening in support of the NCRI AML clinical trials; AML17, AML18, AML19 and LI1.

Nucleic acids are banked from trial material for use in research; locally and internationally.  The group is also involved in research projects within the department and external collaborations.

We process >70  AML samples/month on behalf of the AML national trials (MRC-NCRI-AML trial group funded by CRUK, MRC and Bloodwise) and have over 8000 cryopreserved samples (aliquoted to allow multiple testing).

AML Therapy Resistance Group

The AML Therapy Resistance group is led by Dr Martin Ruthardt. For patients suffering from AML, improvements in the disease outcome can be attributed in the last 3 decades mostly to either improved supportive treatments or life-threatening stem cell transplantation (SCT).

As a consequence even good risk AML patients can be definitively cured only in approx. 60% of cases, whereas adverse risk AML patients have a much lower chance of survival. For elder patients (> 65y), the great majority of leukemia patients, the prognosis is even poorer. Therefore, therapy resistance is the major clinical challenge for patients with AML.

The Ruthardt group is working on three major causes of resistance:

1. Failure of targeting the leukemia maintaining/initiating stem cell (LIC) without final eradication of the source of tumour cells.
2. Aberrant processing and metabolism of RNA with the creation of aberrant long and short non coding RNAs and accompanied by aberrant splicing processes.
3. Aberrant epigenetics (DNA methylation and demethylation) as a cause for increased DNA damaging signals and induction of 2º mutations.

These problems are tackled by proteomics and related bioinformatics, AI and machine learning based on primary stem cell biology in vivo and in vitro.