Cardiff Haematology Acute Myeloid Leukaemia Research Unit
The AML Research Unit encompasses both basic science and translational research coupled with clinical trial activity centred on the prognosis, treatment and chemoresistance of acute myeloid leukaemia (AML).
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
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:
- Failure of targeting the leukemia maintaining/initiating stem cell (LIC) without final eradication of the source of tumour cells.
- Aberrant processing and metabolism of RNA with the creation of aberrant long and short non coding RNAs and accompanied by aberrant splicing processes.
- 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.
Grants last 2 years
- Blood Cancer UK. Project grant exploring NOX2 as a component of multi-target therapy for acute myeloid. Prof Tonks (PI): Prof Darley (Co-app). 2022-2025; £248,000.
- Saudi Arabia Cultural Mission PhD Studentship. The role of hnRNP proteins in leukaemogenesis.PhD Studentship. Prof Tonks (PI), Prof Darley (Co-app). 2021-2025: £146,000.
- Saudi Arabia Cultural Mission PhD Studentship. Identification and validation of novel therapeutic targets and biomarkers in acute myeloid leukaemia. 2021-2025. Prof Darley (PI), Prof Tonks (Co-app). 2021-2025: £142,000.
- Saudi Arabia Cultural Mission PhD Studentship. Role of S100A proteins in AML. 2021-2025. Prof Tonks (PI), Prof Darley (Co-app), Dr Knapper (Co-app). 2021-2025: £142,000.
- Saudi Arabia Cultural Mission PhD Studentship. Re-wiring the metabolism of cancer cells. 2021-2025. Prof Tonks (PI), Prof Darley (Co-app), Dr Knapper (Co-app). 2021-2025: £142,000.
- Specialist Programme Renewal. Targeting the ROS axis. Prof Darley (Co-PI), Dr Tonks (Co-PI), DrKnapper (Co-app). 2016 – 2020. £657,000K. LLR grant number ref: 15018.
- Wellcome ISSF Project grant. Re-wiring the metabolism of cancer cells – therapeutically targeting glycolytic metabolism of blood cancers. Prof Tonks (PI), Prof Darley (co-app). 2020-2022: £37,636.
- Roche £554,000 2022-2024. Zabkiewicz and Ashelford. Providing a Trusted Research Environment tailored for cancer research in Wales
- Cardiff University Research Infrastructure bid £254,000 2021. Zabkiewicz and Ottmann. Development of Miltenyi Prodigy cell manufacturing platform for advanced therapies.
- Health and Care Research Wales £256,674 2021-2023. Zabkiewicz. Investigating Immune cell fitness to determine patient response to Chimeric Antigen Receptor (CAR)T-Cell therapy
- MRC CiC award £50,000 March 2021-Dec 2022 Zabkiewicz and Alvares. Optimising Multiparameter flow cytometry for measuring T cell fitness.
- MRC P2D award £50,000 clonal Haematopoiesis in healthy individuals. Alvares and Ottmann.
- Jazz Pharmaceuticals £331,000 Feb 2020-2022. Alvares and Zabkiewicz: Investigating minimal residual disease maintenance by the tumour microenvironment in Acute Myeloid Leukaemia.
- Celgene £279K Zabkiewicz and Alvares. Feb 2019 -2022 £179,000. Microenvironment modelling of exosome communication in drug resistant AML.
Current clinical trials activity
- AML18 study (phase 3, newly-diagnosed AML in over-60s) - co-chief investigator.
- VICTOR study (phase 3, newly-diagnosed NPM1-mutated AML) – co-chief investigator.
- Member of trial management groups (and pharmacovigilance) for AML19, AML LI-1, PHAZAR, PACES and MITHRIDATE studies.
- MONOCLE study (phase 2 study of Tefinostat in CMML) - chief investigator.
- UK lead investigator for HARBOR (BLU-263-1201), Astex TAS1553-01 and Kura KO-539 studies.
- Lead of Cardiff Trials Acceleration Programme (TAP) centre – currently funded by Cure Leukaemia.
- Lead for Early Phase Haematology Trials in Welsh Cancer Research Centre (WCRC).
- Local PI for MANIFEST-1, MANIFEST-2, Cell Centric CCS-1477-02, Novartis CPDR001X2105, PROMISE, ACHIEVE, GS-352-0101, GS-546-5847, Kartos KRT-232-102, GlycoMimetics GMI-1271-301).
- Chief Investigator on CHIP study (Clonal haematopoiesis in the Welsh population: a study to identify environmental factors and genetic events that determine risk of progression to cancer and heart disease).
- Chief Investigator on microenvironment research study.
- Principal Investigator on M19-708 study: A randomised open label two arm multi-centre phase III study of venetoclax and azacytidine versus best supportive care as maintenance for patients with AML in first remission after conventional chemotherapy (VIALE-M).
- Co-investigator on AML studies active in the department of haematology University Hospital of Wales.