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Cardiff Haematology Acute Myeloid Leukaemia Research Unit

The AML Research Unit, within the Section of Haematology, is led by Professor Oliver Ottmann and encompasses both basic science and translational research coupled with clinical trial activity centred on the prognosis, treatment and chemoresistance of acute myeloid leukaemia (AML).

Our aim is to learn more about the biology of AML, discover and characterise new therapeutic targets and to test and identify better treatments for AML patients.

AML research at Cardiff comprises a number of groups with national and international reputations in haematological oncology; we consistently receive outstanding ‘International Profile Ratings’ in UK based research assessment exercises.

As part of the CRUK funded Experimental Cancer Medicine Centre (ECMC) a translational programme identifies candidate agents for inclusion in the national trials and supports associated biobanking and biomarker activity as well as early phase clinical trials.

The UK NCRI trials in Acute Myeloid Leukaemia are sponsored by Cardiff University, and run by the Centre for Trials Research. More details can be found on the Centre website.

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 Oliver 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 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 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:

  1. Failure of targeting the leukaemia maintaining/initiating stem cell (LIC) without final eradication of the source of tumour cells
  2. 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 to 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.

Current funding

  • 2016–2019 LRAW Group Leads J Zabkiewicz and C A Alvares (Co-PIs).  Project:  The role of beta catenin in the bone marrow protection of acute leukaemia cells from chemotherapy.
  • 2015-2018 Saudi Arabia Gov Group Leader A Tonks. PhD studentship: Role of S100A proteins in AML.
  • 2015-2018 Bloodwise Group Lead S Knapper.  Clinical Trial:A phase 2 study of the monocyte-targeted histone deacetylase inhibitor Tefinostat (CHR-2845) in chronic myelomonocytic leukaemia.
  • 2015-2018 Bloodwise Group Leads R L Darley and A Tonks (Co-PIs). Programme:  Targets for Treatment in AML: Targeting the ROS axis.
  • 2015-2016 Cardiff CRUK Centre Group Lead J Zabkiewicz. Project:  Investigating stromal mediated protection of AML blasts via alterations in ERK signalling.
  • 2014-2016 Bloodwise Lead S Knapper.  TAP Trials Acceleration Programme.
  • 2014-2016 ONO Pharmaceuticals Lead S Knapper. Project: Evaluation of TAM receptor kinase inhibitor in acute myeloid leukaemia.
  • 2013-2017 CRW Lead R L Darley. PhD Studentship:  Mechanisms deregulating Wnt signalling in AML.
  • 2013-2017 Tenovus Lead A Tonks. PhD Studentship: The role of ROS and glycolytic metabolism in AML.
  • 2012-2017 CRUK Group Leads J Chester and O Ottmann.  Project: Experimental Cancer Medicine Centre.

Clinical trials

Dr Knapper’s list of current trial activity:

  • MONOCLE study (phase 2 study of Tefinostat in CMML) - chief investigator.
  • AML18 study (phase 3, newly-diagnosed AML in over-60s) - co-chief investigator.
  • Member of trial management groups (and pharmacovigilance) for AML19, AML LI-1 studies and PHAZAR studies.
  • UK lead investigator for MIRROS and Decitabine/CD123 Ab studies.
  • Local PI for CAMELLIA, RAVVA, RESPONSE, MAJIC, PERSIST, SIMPLIFY, AC220-007 studies.

Dr Alvares’ list of current trial activity:

  • SOPRA study (phase 2 study of Selinexor vs physicians choice in relapsed or refractory AML) – principal investigator.
  • Co-investigator and involved on all the AML trials which includes AML 19, AML 18, LI-1, CATAPULT, CAMELLIA, AC220-007.
  • A programme of development for older patients. Synta Ltd. 2014-2018.

Academic staff

Professor Oliver Ottmann

Professor Oliver Ottmann

Professor and Head of Haematology, Division of Cancer and Genetics

Email:
ottmanno@cardiff.ac.uk
Telephone:
+44 (0)29 2074 2375
Professor Richard Darley

Professor Richard Darley

Professor

Email:
darley@cardiff.ac.uk
Telephone:
+44 29207 45507
Dr Alex Tonks

Dr Alex Tonks

Reader, Division of Cancer and Genetics

Email:
tonksa@cardiff.ac.uk
Telephone:
+44 29207 42235
Dr Steven Knapper

Dr Steven Knapper

Clinical Reader

Email:
knappers@cardiff.ac.uk
Telephone:
+44 29207 45379
Dr Martin Ruthardt

Dr Martin Ruthardt

Senior Lecturer in Haematology, Division of Cancer and Genetics

Email:
ruthardtm@cardiff.ac.uk
Telephone:
+44 (0)29 2074 2307
Dr Joanna Zabkiewicz

Dr Joanna Zabkiewicz

Research Associate

Email:
zabkiewiczj1@cardiff.ac.uk
Telephone:
+44 29207 42499
Amanda Gilkes

Amanda Gilkes

Research Associate

Email:
gilkes@cardiff.ac.uk
Telephone:
+44 29207 44522