Cardiff Haematology Acute Myeloid Leukaemia Research Unit

Ymchwil

Cardiff AML Target Discovery and Translation Research Group

This group is co-lead by Professor Richard Darley and Dr Alex Tonks.  Together with our clinical colleagues (Professor Ottmann and 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, the S100 family of calcium binding proteins and novel factors regulating β-catenin translocation.

Pre-clinical Drug Development Group

The pre-clinical drug development group is part of the Cardiff Experimental Cancer Medicine Centre (ECMC).  The group is co-led by Dr Joanne Zabkiewicz and Dr Caroline Alvares with the principal directive of developing novel therapeutics that are active against primary leukaemia cells which have been demographically, cytogenetically and molecularly characterised with clinical outcome data. Current research of the group focuses on the development of new models of drug resistance and relapse in AML, particularly with regard to alterations in the tumour microenvironment. The bone marrow microenvironment is a key player in mediating chemotherapy resistance, and recent evidence has highlighted its role in providing protection for AML cells leading to disease relapse. 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 a rationale for novel drug combinations in clinic.

Clinical Development Group

In addition to working closely with the pre-clinical group, 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); Following funding by Bloodwise, Dr Knapper is the chief investigator of the MONOCLE study (UK phase 2 study of Tefinostat in CMML) which will open at 12-15 UK hospital sites in 2016.  Dr Knapper is currently investigating monocyte-targeted HDAC inhibition (SEC) and TAM-kinase inhibition (ONO Pharma).

AML Research Tissue Bank

The AML Research Tissue Bank, established in 2013 and sponsored by Cardiff University, is led by Professor Ottmann and managed by Dr Paul White.  We process >20  AML samples/month on behalf of the AML national trials (MRC-NCRI-AML trial group funded by CRUK, MRC and Bloodwise) and have over 1200 cryopreserved samples (aliquoted to allow multiple testing).  All patients are linked to the AML clinical trials database which contains information on cytogenetics, patient demographics, clinical outcome and in the near future many will have information on Exome sequencing.  The AML research tissue bank Governance Committee holds regular meetings to consider project applications made to the bank.  Dr Paul White is the current Human Tissue Officer for the Section of Haematology and ensures that banked tissue complies with the Human Tissue Act according to the regulations set out by the Human Tissue Authority.  He is also the current contact for applications that wish to make use of tissue form the bank.

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.

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 3 decades can be attributed mostly to either improved supportive treatments or life-threatening stem cell transplantation (SCT). As a consequence even AMLs classified as intermediate risk can be definitively cured only in approx. 60% of cases, whereas adverse risk AML patients have a much lower chance of survival. A situation which is even worse in elder patients (> 65y), which represent the great majority of leukaemia patients. Therefore therapy resistance is the major clinical challenge for patients with AML.
Two major causes of resistance can be hypothesised:

• failure of targeting the leukaemia maintaining/initiating stem cell (LIC) without final eradication of the source of tumour cells
• clonal evolution - the original monoclonal (originating from one malignant cell) disease develops upon therapeutic pressure. The new clones differ from the starting clone by exhibiting different stem cells and resistance features.

The role of clonal evolution and lack of eradication of the LIC in primary or secondary resistant patients is still widely unclear. Hence we want 1.) disclose mechanisms of resistance in samples from primary AML patients, by studying commonalities and differences regarding numbers of subclones and the biology of single subclones and 2.) develop novel therapy approaches able not only to reduce clonal evolution but also to eradicate the LIC subpopulation, the only way to definitively cure patients with AML.