Cardiff Haematology Acute Myeloid Leukaemia (AML) 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 colleagues 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 / transcriptomics / 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 RUNX proteins, NFIC family of proteins, NOX oxidases, carbohydrate metabolism, the S100 family of calcium binding proteins and novel factors regulating β-catenin activity.

Haematological malignancy microenvironment group

The ‘microenvironment’ group is co-led by Dr Joanna Zabkiewicz and Dr Caroline Alvares. Our principal focus is the pre-clinical and translational development of novel therapeutics that are active against primary patient leukaemia cells as part of Cardiff ECMC early phase pipeline.

We are currently running several translational clinical studies using demographically, cytogenetically, and molecularly characterised serial sampling to assess potential biomarkers of clinical response.

Current research in the group has identified a key role for the bone marrow microenvironment in drug resistance and relapse of AML. Bone marrow support cells called mesenchymal stem cells (MSCs) help to provide structure and a protective environment for haematopoietic stem cells to grow.

Our research is investigating how abnormalities in adhesion molecules, cytokine and exosome secretion in a patient’s microenvironment may make them resistant to therapy and render the bone marrow unable to support normal donor stem cell growth.

We have recently expanded our studies into the immunosuppressive microenvironment of both AML and DLBCL CART patients and its ability to suppress anti-cancer immune cells with an aim to identify those patients likely to respond to immunotherapy approaches.

We have developed several long term and 3D co-culture models of the bone marrow microenvironment in which we can study cell-to-cell behaviours such as adhesion, cell growth, immunosuppression, and stem cell 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 the rationale for novel microenvironment-based therapy combinations in the clinic.

Clinical Development Group

Professor Knapper is a clinical academic haematologist based at the University Hospital of Wales where he leads the haematological cancer multi-disciplinary team, specialising in treatment of AML and myeloproliferative neoplasms. In addition to working closely with the pre-clinical group, he 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.

Professor Knapper is also a member of the Cardiff AML Target discovery and translation research group and is currently collaborating with the Cardiff Medicines Discovery Institute in developing KAT2A Protacs in AML. He 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) and developed the monocyte-targeted histone deactylase inhibitor tefinostat in AML and chronic myelomonocytic leukaemia, leading to a Blood Cancer UK-funded phase 2 clinical trial in CMML for which he was chief investigator.

He is currently involved in the development of clinical research at a national level as deputy chair of the UK AML Clinical Studies Group, within which he leads the development of international clinical trials for newly-diagnosed patients who are fit for intensive therapy, and membership of the Myeloproliferative Neoplasms Clinical Study Group.

He is extensively involved in haematology early phase trials as Deputy Clinical Director of the UK Trials Acceleration Programme (TAP), chair of the ECMC Haematology group and current PI for a rolling programme of studies at the University Hospital of Wales.

Dr Caroline Alvares is a Clinical Senior Lecturer in Haematology at Cardiff University & Honorary Consultant Haematologist with expertise in the diagnosis and treatment of AML and myeloid disorders. She has been chief investigator and principal investigator on a number of global AML trials from early to late phase at the University Hospital of Wales.

She has a background PhD in AML and co-leads the AML microenvironment group enabling unmet need within the clinical setting to be addressed within the research group to improve current prognostics and therapeutics.

She is also chief investigator of the CHIP study which investigates clonal haematopoiesis and risk factors in the general population, an antecedent to the onset of MDS, AML and other cancers.

Also see clinical trial activity in ‘projects’.

AML Therapy Resistance Group

The AML Therapy Resistance group is led Dr Martin Ruthardt.  For patients suffering from AML improvements in the disease outcome in the last three decades can be attributed 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 approximately 60% of cases, whereas adverse risk AML patients have a much lower chance of survival. For elder patients (> 65y), the great majority of leukaemia 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 leukaemia 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 noncoding 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.