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Staff Profile

Dr Frederik van Delft

Clinical Senior Lecturer/Hon.Consultant

Background

Roles and Responsibilities

I have a joint appointment as Clinical Senior Lecturer at Newcastle University Centre for Cancer and Honorary Consultant in Paediatric Oncology at the Great North Children's Hospital providing a clinical service for young people with leukaemia or lymphoma. The remit of my research programme is explained under the research section of this webpage.

Qualifications

  • 1994 MD, Katholieke Universiteit Leuven, Belgium
  • 2000 CCT in Paediatrics, Vrije Universiteit Brussels, Belgium
  • 2000 Full and specialist registration in Paediatrics (GMC registration number 4452924)
  • 2008 PhD, Queen Mary University of London, England
  • 2013 Fellow of the Royal College of Paediatrics and Child Health (FRCPCH)

Previous Positions

  • 1995-1996 Clinique Baron Lambert, Brussels, Belgium, Specialist Registrar in Paediatrics
  • 1996-1997 Universitair Ziekenhuis Brussel, Belgium, Specialist Registrar in Paediatrics
  • 1997-1998 Great Ormond Street Hospital for Sick Children, London, Specialist Registrar in Paediatrics and Paediatric Haematology & Oncology
  • 1998-2000 Universitair Ziekenhuis Brussel, Belgium, Specialist Registrar in Paediatrics and Paediatric Haematology & Oncology
  • 2000-2001 Harley Street Clinic, London, Resident Medical Officer in Paediatrics
  • 2001-2006 Royal London Hospital & Queen Mary University of London, Clinical Research Fellow in Paediatric Oncology and PhD student
  • 2006-2007 University College Hospital, London, Clinical Research Fellow in Paediatric Oncology
  • 2007-2013 Royal Marsden Hospital & Institute of Cancer Research, Postdoctoral Fellow in Paediatric Oncology

Memberships - National

  • CCLG
  • NIHR CRN CYP TYA Subspecialty Research Lead
  • Childhood Leukaemia Research UK

Memberships - International

  • IBFM / SIOPE Childhood Leukaemia Study Group - Resistant Disease Committee
  • International Leukaemia Tumour Board (iLTB)
  • Hem-iSmart Steering Committee
  • ITCC Hema Committee
  • EHA
  • SOHO

Languages

Dutch, English, French

Research
"Improving outcomes for patients with drug resistant T-cell haematological malignancies."


My goal as an academic paediatric oncologist is to develop precision medicine therapies for children with high-risk leukaemias to improve clinical outcomes and minimise toxicities.


I trained in the laboratories of Prof Vaskar Saha at Queen Mary University of London and Prof Sir Mel Greaves at the Institute of Cancer Research, who gave me a solid grounding in leukaemia research and its translation into clinical management. Since moving to Newcastle University Centre for Cancer, I have developed a research programme which focuses upon identification of targeted therapeutic strategies for childhood leukaemias via (1) characterisation of signal transduction and survival pathways and preclinical testing of small molecule inhibitors in acute lymphoblastic leukaemia (ALL) and (2) early phase clinical testing of molecularly-targeted therapies for children with leukaemia through the Innovative Therapies for Children with Cancer (ITCC) and European Society for Paediatric Oncology (SIOPe) consortia.

 

Clinical unmet need


T-cell acute lymphoblastic leukaemia (T-ALL) is diagnosed in 90 children and teenagers living in the United Kingdom each year. Most of these patients can expect long-term survival with currently available treatment protocols. The outcome for patients with recurrent or refractory (drug resistant) T-ALL however remains unfavourable and this patient group represents a clinical unmet need.


In order to address this unmet clinical need, my laboratory has developed expertise in the interrogation of drug resistant ALL in unique, clinically relevant, in vitro and in vivo models, including OP9-DL1 co-cultures, high throughput assays, CRISPR/Cas9 knock-out approaches, single cell RNA sequencing, mass cytometry, and BH3 profiling. Our TTeam is based at the Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer. The infrastructure at Newcastle University and Great North Children’s Hospital provides a wide range of state-of-the-art services to allow us to interrogate the biology of T-lineage derived malignancies and translate this knowledge into delivering improved therapies in early and late phase clinical trials.


Current projects


Targeting the preTCR-LCK axis in T-ALL. Aberrant activation of developmental pathways frequently underlie the development of cancer. Using an shRNA screen against components of the pre T Cell Receptor (preTCR) pathway, we have identified a critical role for the signalling molecule LCK in proliferation of human T-ALL in mouse models. [Figure 1] Excitingly, glucocorticoid resistance in T-ALL cells could be reversed when combining inhibition of LCK with dexamethasone. Inhibition of LCK can be effectively achieved using the second generation tyrosine kinase inhibitor dasatinib, which is already in use for the treatment of BCR-ABL1 positive ALL. We are currently working to understand the mechanism underlying the reversal of drug resistance, as well as identify response biomarkers, with the aim to include this novel therapy in early phase trials. The combination of dexamethasone and dasatinib will be prospectively tested in the early phase trial platform Hem-iSmart which is expected to open for recruitment in 2024.


Optimisation of response to (re-)induction therapy. The initial phase of clinical treatment for patients with T-ALL consists of a four-drug induction regimen containing dexamethasone, vincristine, asparaginase and daunorubicin (VXLD). Response to this induction treatment, as measured by real-time genomic PCR or flow cytometry, is currently the only reliable predictor for outcome. Understanding mechanisms that provide resistance against this induction regimen has the potential to improve outcomes. We have developed a preclinical model of induction therapy and have employed a functional genomic screen, using CRISPR/Cas9 technology, to unravel mechanisms of resistance to VXLD treatment in vitro and in vivo. We have identified differential sgRNA representation after VXLD treatment which represents tangible drug targets which are subject to ongoing validation studies. [Figure 1] The aim is to develop an optimised re-induction platform (VXLD + experimental drug) which will improve response to treatment and outcomes for patients with relapsed or refractory T-ALL or Lymphoblastic Lymphoma (LBL).


Targeting drug resistant Minimal Residual Disease. The presence of minimal residual disease (MRD) after re-induction therapy is prognostic for patient outcomes. We, and others, have shown that the majority of ALL relapses are clonally related to the initial leukaemia presentation suggesting that the MRD cell population provides the origin of relapse. This implies that targeted therapies against the MRD population might improve response to treatment and prevent relapse.


My team has joined forces with Professor Julie Irving at Newcastle University to develop and undertake a team science approach to develop specific therapies targeting MRD cell populations. We have undertaken single cell functional profiling studies (CyTOF) in clinical patient samples collected after VXL(D) induction therapy. These analyses revealed insight into cellular behaviours allowing escape from therapy and identified bona fide drug targets in BCP-ALL and T-ALL. We are using our preclinical model of induction therapy to validate these observations and aim to translate targeted therapies into early phase clinical trials.


ALLTogether T-ALL Special Interest Group. Children and young adults with newly diagnosed ALL are eligible for recruitment to the international ALLTogether trial. Professor Sofie Degerman (Umea University, Sweden) and I chair a newly formed special interest group within this trial. The remit of this group of clinicians and scientists is to undertake trial associated research to improve risk stratification and outcomes for patients with high risk T-ALL. In a joint effort with international collaborators, we have been awarded FKC (Fighting Kids Cancer) project funding to generate patient derived xenografts and perform comprehensive genetic, proteomic and drug profiling of these PDX samples. Using an artificial intelligence (AI) approach, we will generate Digital Twins to identify novel drug targets in high risk T-ALL patients. The Comparative Biology Centre at Newcastle University will support this exciting project with generation of PDX samples.



Figure 1. Graphic display of our experimental set-up for the identification of mechanisms of drug resistance and translation into clinical management.


Current TTeam members

Dr Alistair Poll Research Associate

Mr Mankaran Singh NUCancer CRUK PhD student

Dr Yashashree Gupta Clinical Research Fellow

Ms Martina Mattioli MRC DiMEN Doctoral Training Partnership


Previous members

Dr Beth Adamson Research AssociateDr Melanie Beckett - Newcastle University Centre for Cancer

Dr Yuzhe Shi - MSK Cancer Center, USA

Dr Anja Krippner-Heidenreich - Prinses Maxima Centrum, The Netherlands 

UG and MRes students


Collaborations

Professor Julie Irving

Professor Christine Harrison, Professor Anthony Moorman, Dr Claire Schwab (LCRG)

Dr Lisa Russell and Dr Simon Bomken

Dr Gavin Cuthbert, Centre for Life, Newcastle University

Professor Pieter Van Vlierberghe, Ghent University, Belgium (in memoriam)

Prof Jean Pierre Bourquin, Dr Beat Bornhauser, Zurich, Switzerland

Professor Andreas Kulozik, Heidelberg, Germany

Dr Jun J Yang, St Jude Children's Research Hospital, Memphis 


Funders - present and past

Newcastle University

Children's Cancer North

JGWP

CCLG Little Princess Trust

Cancer Research UK

European Science Foundation - Fighting Kids Cancer

GOSH Charity

Bright Red

Action Medical Research

Children with Cancer

Chinese Government

Team Lewis Trust


We wish to thank all patients and families who have generously donated leukaemia samples to allow for these studies.


Teaching

I supervise undergraduate, master and PhD students at the Wolfson Childhood Cancer Research Centre, and provide bedside clinical teaching to medical students at the Great North Children's Hospital.

Current students

  • Mr Mankaran Singh - PhD student
  • Mr Ozcan Gulbey - PhD student (second supervisor)
  • Mr Tudor Dinca - MSci student
  • Ms Emily Parsons, Molly Purvis - MSc students
  • Ms Sarah Orrell, Laras Prakoso - MRes students

Previous students

PhD

  • Dr Yuzhe Shi
  • Dr Melanie Beckett

UG

  • Anna Wong
  • Beth Poole
  • Rickard Phillips

MRes

  • Anukrati Nigam
  • Edward Hayter
  • Andrew Cairns
  • Nicole Cripps
  • Khaireen Idzham
  • Beth Poole
  • Deborah Adekanmbi
  • Melissa Lee
  • Hannah Elkatkat

MSc

  • Melody Yu
  • Serena Au

I have contributed a chapter titled "The biology of childhood leukaemia" for the 2nd edition of the Oxford specialist handbook in Paediatric Haematology & Oncology.


Publications