Cardiff Haematology Acute Myeloid Leukaemia (AML) Research Unit

The AML Research Unit encompasses both fundamental 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 Alex Tonks and encompasses both fundamental 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 several 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.

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:

Failure of targeting the leukaemia 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 noncoding 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.

Projects

Grants last 2 years

(Tonks/Darley)

Blood Cancer UK. Project grant. Exploring NOX2 as a component of multi-target therapy for acute myeloid leukaemia. Prof Tonks (PI), Dr Khorashad (Co-PI), Prof Darley (Co-app), Dr Rodrigues (Co-app). 2022-2025: £248,503.
Blood Cancer UK. Project grant. Zeb1 mediated regulation of mouse and human leukaemic initiating/stem cells (LICs) in acute myeloid leukaemia. Dr Rodrigues (PI), Prof Tonks (Co-App). 2024-2027: £250,000.
LMUK. Small project grant. Understanding ZEB1 mediated regulation in human AML. Dr Rodrigues (PI), Prof Tonks (Co-App). 2024-2025: £35,000.
HealthCare Research Wales. 2022. Understanding mechanisms of NFIC in regulating AML development and progression. PhD Studentship. Prof Tonks (PI), Dr Hywel Williams (Co-App), Prof Darley (Co-app). 2022-2025: £96,000.
KFMC IRFA. Project Grant. Identification of S100A4 binding partners in Acute Myeloid Leukemia (AML). Prof Hamza (PI), Prof Tonks (Co-app), Prof Darley (Co-app). 2022-2024: £44,562.
Saudi Arabia Cultural Mission PhD Studentship. 2021. Re-wiring the metabolism of cancer cells – therapeutically targeting glycolytic metabolism of blood cancers. PhD Studentship. Prof Tonks (PI), Prof Darley (Co-app). 2021-2025: £154,000.
Saudi Arabia Cultural Mission PhD Studentship. 2021. Mechanisms underlying the required expression of S100A4 for proliferation and survival of AML blasts. PhD Studentship. Prof Tonks (PI), Prof Darley (Co-app). 2021-2025: £149,175.
Saudi Arabia Cultural Mission PhD Studentship. 2021. The role of hnRNP proteins in leukaemogenesis. PhD Studentship. Prof Tonks (PI), Prof Darley (Co-app). 2021-2025: £146,500.
Saudi Arabia Cultural Mission PhD Studentship. Identification and validation of novel therapeutic targets and biomarkers in acute myeloid leukaemia. Prof Darley (PI), Prof Tonks (Co-app). 2021-2025: £142,000.

(Zabkiewicz/Alvares)

MRC DPFS grant. Investigating KAT2A PROTACs targeting the differentiation of blasts and leukemic stem cells for the treatment of Acute Myeloid. Leukaemia. Ward (PI) and Zabkiewicz (Co-I): 2023-2026. £1.8M.
MRC IPOCH PhD studentships. Use of Cancer Patients Digital Twins to Investigate disease fragmentation and its impact on drug response in AML trials.
CRUK. Cardiff ECMC centre. Ottmann, O (PI); Knapper S (co-I, Zabkiewicz (Co-I). 2023-2028, £2.4M.
Roche. Project. Providing a Trusted Research Environment tailored for cancer research in Wales. Zabkiewicz (PI) and Ashelford.2022-2024: £554,000.
Health and Care Research Wales. Project. Investigating Immune cell fitness to determine patient response to Chimeric Antigen Receptor (CAR)T-Cell therapy. Zabkiewicz (PI). 2021-2023: £256,674.

(Knapper)

CRUK. Clinical Trial Award. Optimise-FLT3 – optimising therapy for patients with FLT3-mutated acute myeloid leukaemia. 2024-2031, £2.01m (PI) CRUK. Cardiff ECMC centre (co-PI).
NIHR Health Technology Assessment Programme. PROPEL: Evaluation of personalised prehabilitation in acute myeloid leukaemia. 2022-27, £2.57m (co-applicant).
Blood Cancer UK. Molecular characteristation of patients with NPM1-mutated AML who enter deep remission without intensive chemotherapy: scientific correlates of the VICTOR trial. 2021-23, £249k (co-applicant).
CRUK. VICTOR: Venetoclax or intensive chemotherapy for treatment of favourable risk acute myeloid leukaemia: a molecularly-guided phase 2 study. 2020-25, £942k (co-applicant).

Current clinical trials activity

Professor Knapper

Deputy chair of NCRI Acute Myeloid Leukaemia Working Group
Member of NCRI Myeloproliferative Neoplasms Clinical Studies Group
Deputy Medical Director of UK Trials Acceleration Programme
Co-director of ECMC Haematology group
Optimise-FLT3 study (phase 3 study for newly diagnosed FLT3-mutated AML) – chief investigator
AML18 study (phase 3, newly diagnosed AML in over-60s) - co-chief investigator
VICTOR study (phase 2b, newly diagnosed NPM1-mutated AML in over-55s) – co-chief investigator
Member of trial management groups (and pharmacovigilance) for AML18, AML19, VICTOR, PROMISE, MITHRIDATE, PROPEL and AMMO studies
Local PI for Cell Centric CCS-1477-02, Kura KO0539, MANIFEST-1, MANIFEST-2, FEDORA and INCB 00928-104 studies
Course director of European Haematology Association Clinical Research Training in Haematology (CRTH) programme

Dr Alvares

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).
Principal Investigator on ARC initiative: Real World Evidence study assessing treatment outcomes for AML patients treated with venetoclax.
Co-investigator on AML studies active in the department of haematology University Hospital of Wales.