Key Investigators | UCLH Biomedical Research Centre

Professor Adrienne Flanagan OBE (Theme Co-lead) is a leading UK sarcoma pathologist who defined key mutational pathways and actionable mutations in soft tissue sarcomas, chordoma.

Research

Adrienne Flanagan plays a leading role in characterising sarcomas at a genomic level and introducing biomarkers into clinical practice; the markers include brachyury expression in chordoma, IDH1/2 mutations in chondrosarcoma, FOSL structural alterations in osteoblastoma, and FN1-ACVRA fusions genes in synovial chondromatosis, all of which are now reported in the WHO reference book for diagnosing these tumours.

She works closely with patients and their families and school children affected with sarcoma; giving talks and speaking directly to patients and organising evening sessions for different groups.

Research impact

Our discovery of brachyury (Journal of Pathology 2006; 209(2):157-165) being expression chordoma has led to vaccine trials (by others) and our work, (J Pathol. 2016; 239(3):320-34 has resulted in a clinical trial for patients with chordoma (CI Sandra Strauss).
Prof. Flanagan is working with the Brancale, McFarlane, Wakeman groups to identify novel inhibitors of the Brachyury protein funded by Alderley Park Oncology Development Programme (https://www.alderleypark.co.uk/oncologyprogramme)

Future aims

To establish a strong AI /deep learning research focus in sarcoma and other cancers across the UK building on the Innovate UK funds awarded in 2020 and the Genomics England resource developed over the last 2 decades including the 100,000 Genomes Project
To recruit more trainee pathologists across the UK to enrol in PhDs (building on the initiative that I lead with funding from the Jean Shanks Foundation and the Pathological Foundation).

Key positions and honors

2019 Honorary Doctorate by the Royal College of Surgeons in Ireland
2017 OBE (hon) for contribution to cancer research
2017-20 NIHR Senior Investigator
LEAD – NHSX Bone Pathology Network comprising the 5 bone tumour units in England
Objective: to support, develop and standardise clinical service
2016 LEAD Genomics England Clinical Interpretation Partnership (GeCIP) Sarcoma Domain
Lead for the Innovate UK National Pathology Imaging Collaboration – Sarcoma Network
2017 William Gerald Award: established by the Department of Pathology at Memorial Sloan Kettering Cancer Center to recognize outstanding contributions to research in cancer pathology
2017 Goudie Lecture and Medal awarded to a distinguished active scientist who is making seminal contributions to pathological science and the understanding of disease mechanisms.
2020 Invited to give Pathology Grand Rounds at Johns Hopkins
2014 FMedSci - Elected Fellow UK Academy of Medical Science

Top 5 Publications (since 2015)

Cottone L et al. (2020) Inhibition of histone H3K27 demethylases inactivate brachyury (TBXT) and promotes chordoma cell death. Cancer Research Oct 15;80(20):4540-4551.
Steele CD et al. (2019) Undifferentiated Sarcomas Develop through Distinct. Evolutionary Pathways. Cancer Cell 18;35(3):441-456.e8.
Ly Pet al. (2019) Chromosome Segregation Errors Promote a Diverse Spectrum of Simple and Complex Genomic Rearrangements. Nature Genetics 51(4):705-71.
Fittall M et al. (2018) Recurrent rearrangements of FOS and FOSB define osteoblastoma. Nature Communications 9(1)2150: 1-6.
Tarpey Pet al. (2017)The driver landscape of sporadic chordoma. Nature Communications 8(890):1-6.

Professort Gert Attard is a medical oncologist developing ctDNA technologies to monitor immunotherapy studies in prostate cancer and to guide treatment decision-making.

Research

Despite significant initial responses to therapy, treatment resistance remains the hallmark of metastatic disease. Prof. Attard’s group is a multi-disciplinary team focusing on studying treatment resistance in advanced prostate cancer. Since starting up five years ago, the group has been integrating solid tumour and circulating cell-free DNA genomics, transcriptomics and epigenomics generated from carefully annotated clinical trial cohorts with functional studies to improve prostate cancer patient management. Using these approaches, the aim is to identify cancer vulnerabilities to be exploited therapeutically and design clinical trials of biomarker-directed strategies for rational treatment selection and sequencing.

Research Impact

Some of the group’s recent work used plasma DNA to track androgen receptor (AR) gene aberrations in advanced prostate cancer patients and identified a strong association between plasma AR aberrations and resistance to second-line hormonal treatments. They also identified a plasma DNA methylation signature associated with the presence of circulating prostate cancer DNA. These findings and others have led to the initiation of the PARADIGM study (NCT04067713, Plasma Analysis for Response Assessment and to Direct the manaGement of Metastatic prostate cancer) evaluating if the detection of circulating prostate cancer DNA is associated with treatment response. My research has contributed to the licensing approval of abiraterone for metastatic prostate cancer, used widely in the NHS and globally.

Future plans

The group have integrated our plasma DNA analysis into multiple clinical trials, including the national platform STAMPEDE trial for men starting androgen deprivation therapy. This complements our work leading the genomic analysis of solid tumour material from this trial as part of the STRATOSPHERE consortium, aiming to characterise hormone-naïve prostate cancer from men with metastatic prostate cancer. We are also part of multiple ongoing international efforts working to implement plasma analysis into clinical practice. In the PCF-SELECT international consortium we are developing a clinically useful plasma DNA targeted NGS assay and in the CRUK Accelerator Award funded PRIME project we are working to integrate all that we have learnt during these past years into a plasma based multimodal test for prostate cancer.

Top 5 publications (since 2015)

Attard, G et al. Abiraterone acetate plus prednisolone (AAP) with or without enzalutamide (ENZ) added to androgen deprivation therapy (ADT) compared to ADT alone for men with high-risk nonmetastatic (M0) prostate cancer (PCa): combined analysis from two comparisons in the STAMPEDE platform protocol. Annals of Oncology (2021) 32 (suppl_5): S1283-S1346.
Wu A et al. Genome-wide plasma DNA methylation features of metastatic prostate cancer. J Clin Invest. 2020 Apr 1;130(4):1991-2000.
Attard G et al. Assessment of the Safety of Glucocorticoid Regimens in Combination With Abiraterone Acetate for Metastatic Castration-Resistant Prostate Cancer: A Randomized, Open-label Phase 2 Study. JAMA Oncol. 2019 Aug 1;5(8):1159-1167.
Romanel A et al. Plasma AR and abiraterone-resistant prostate cancer. Sci Transl Med. 2015 Nov 4;7(312):312re10.
Carreira S et al.Tumor clone dynamics in lethal prostate cancer. Sci Transl Med. 2014 Sep 17;6(254):254ra125.

Positions and Honors

2019 Chair of the NCRI advanced prostate cancer UK Clinical Study Group
2018 - ongoing John Black Charitable Foundation Chair of Oncology, University College London
2017 Cancer Research UK Future Leaders Award
2016 - ongoing Cancer Research UK Advanced Clinician Scientist Fellowship
2016 Chair of GU (prostate) Scientific Committee ESMO Annual Meeting
2014 - ongoing GU associate editor, Annals of Oncology
2013 - 2018 Team Leader, Centre for Evolution and Cancer, The ICR and Honorary Consultant, Royal Marsden, London

John Bridgewater is an oncologist established national centre in biliary cancers and headed international collaborative trials.

Research

Professor Bridgewater’s research is based on developing clinical trials and the translational outcomes of those studies. In colorectal cancer this were consented on the New EPOC study for operable colorectal liver metastasis. (1) These data define the international standard of care (SoC) for these patients and through a collaboration with the MRC funded SCORT consortium we are about to release molecular data defining treatment outcomes, further refining the SoC. Similarly. I have had collaborations with Queen Mary's further defining the natural history of metastatic colorectal cancer. These data will describe a novel molecular classification of colorectal cancer and comparative treatment benefit, informing a paradigm shift in clinical management.

Research Impact

In biliary tract cancer I have been the chief investigator for 3 clinical studies defining the role of chemotherapy in the adjuvant, first-line and second-line advanced disease therapies. (2-4) We are in the process of assembling and analysing tumour material to describe the molecular natural history of these malignancies. Studies in preparation include an umbrella study in advanced disease investigating targeted therapies. These studies will place translational outcomes at their core, permitting personalised therapy for all patients with biliary tract cancer.

Future Plans

Central to these studies is an academically driven clinical practice that uses molecular diagnostics as the foundation for patient management with which close collaboration with genomics research (through Genomics England for which I am the upper gastrointestinal (UGI) lead and the genomic laboratory hubs) and the clinical research framework (primarily the National Cancer research Institute, the UGI study group of which I chair).

Top 5 publications (since 2015)

Bridgewater JA et al. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial. The Lancet Oncology. 2020:S1470-2045(19)30798-3.
Primrose JN et al. Capecitabine compared with observation in resected biliary tract cancer (BILCAP): a randomised, controlled, multicentre, phase 3 study. Lancet Oncol. 2019.
Valle J et al. Cisplatin plus Gemcitabine versus Gemcitabine for Biliary Tract Cancer. N Engl J Med. 2010;362(14):1273-81.
Lamarca A, et al. Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial. The Lancet Oncology. 2021.

Professor Mark Emberton OBE, Dean of UCL Medical School is also Professor of Interventional Oncology at UCL and Honorary Consultant Urologist at University College Hospitals NHS Foundation Trust. He is also a Founding Pioneer of Prostate Cancer U and has established the role of magnetic resonance Imaging (MRI) in the diagnostic pathway for prostate cancer.

Research

Early detection of prostate cancer
Creation of novel classes of therapy for men with prostate cancer that are better tolerated and more easily administered
Methodological innovation in the conduct of clinical trials that assess complex interventions

Research Impact

Emberton has transformed the way one of the most common cancers – prostate cancer – is both diagnosed and treated. The result is that millions of men every year benefit from (1) more accurate diagnoses and (2) novel treatments that cause significantly fewer side-effects. He has done this by taking an idea through to a series of clinical trials to build up sufficient evidence to change clinical opinion. As a result of his leadership of two large research groups the clinical trials known as PROMIS (Lancet, 2017) and PRECISION (NEJM, 2018) were published and used by NICE to recommend that imaging in the form of MRI be offered to all patients undergoing prostate biopsy (March 2019). The result has been world-wide adoption with benefits to 5 million men every year. These benefits include avoidance of unnecessary biopsy, more accurate biopsy, fewer important cancers missed, less harm and less cost overall.

Emberton also noted that the information obtained from the MRI could be used to create a new form of treatment that aims to treat the cancer (in a focal manner) and preserve healthy tissue at the same time. Mark then designed and conducted a number of clinical studies (early and late phase) to evaluate the safety and effectiveness of this new approach. Like MRI, focal therapy has now achieved world-wide adoption and had given thousands of men the opportunity to avoid the urinary leakage and sexual side-effects that are associated with standard whole-gland treatments.

Future plans

To deliver on INDEX (MRC/CRUK £6.3million) risk stratification study in order to create new prognostic and predictive models
To lead innovation in early cancer detection as Chair of CRUK’s ACED (£30million) Programme
To help set up a modern image-based prostate cancer screening programme in the UK

Top 5 publications (since 2015)

Ahmed HU et al. PROMIS study group. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet. 2017 Feb 25;389(10071):815-822.
Kasivisvanathan V et al. PRECISION Study Group Collaborators. MRI-Targeted or Standard Biopsy for Prostate-Cancer Diagnosis. N Engl J Med. 2018 May 10;378(19):1767-1777.
Azzouzi AR et al. Padeliporfin vascular-targeted photodynamic therapy versus active surveillance in men with low-risk prostate cancer (CLIN1001 PCM301): an open-label, phase 3, randomised controlled trial. Lancet Oncol. 2017 Feb;18(2):181-191.
Ahmed HU et al. Focal Ablation Targeted to the Index Lesion in Multifocal Localised Prostate Cancer: a Prospective Development Study. Eur Urol. 2015 Dec;68(6):927-36.
Guillaumier Set al. A Multicentre Study of 5-year Outcomes Following Focal Therapy in Treating Clinically Significant Nonmetastatic Prostate Cancer. Eur Urol. 2018 Oct;74(4):422-429.

Key positions held

Dean UCL Faculty of Medical Science
Professor of Interventional Oncology, Division of Surgery UCL
Honorary Consultant Urologist at UCH NHS Trust

Adele Fielding is a haemato-oncologist and leading international triallist in ALL

Research Theme

The overall goal of my work is to improve the outcome for adults with acute lymphoblastic leukaemia (ALL). As a clinician-scientist, my approach is a combination of clinical trial work and translational science. I have a particular interest to uncover the reason(s) why children are routinely cured of ALL whereas this is often not the case for adults.

High impact examples

Practice-changing findings from clinical trials which I led in the UK a) the UKALLXII/ECOG2993 trial provided the largest ever study of cytogenetics in ALL defining genetic biomarkers which is used to stratify ALL internationally b) NICE approval of imatinib for BCR-ABL1+ ALL c) EMA and NICE approval of pegylated asparaginase d) collaboration with Amgen on numerous trials of blinatumomab as UK-PI has led to EMA and NICE approval of this agent for several indications in the UK.
Identification of Cancer-Associated fibroblasts in ALL: We showed that traditional, reactive oxygen species-inducing chemotherapies such as daunorubicin and cytarabine can covert bone marrow mesenchymal stromal cells to cancer-associated fibroblasts, which in turn creates a therapy-resistant niche in which ALL cells survive by receiving mitochondria from the altered stromal cells, via tunnelling nanotubes.
Established minimal residual disease (MRD) testing by immunoglobulin heavy chain/T cell receptor gene re-arrangement identification and quantification (Ig/TCR) as the standard of care for adults in the UK: My lab has been the central lab for numerous clinical trials: UKALL14, UKALL60+, UCL- and KCL-based chimeric antigen receptor T cell trials, SeluDex trial, ALL-RIC trials. My lab won the OneUCL award for teamwork in 2020

Future plans

I am in the process of developing the academically-led UKALL15 trial I will be the CI. My research laboratory is completing work, together with key collaborators Anthony Moorman (Newcastle) and Elli Papaemmanuil (Memorial Sloane Kettering Cancer Centre) on our CRUK-funded program “Personalising therapy for adult ALL” Our key objectives for the programme are to (1)discover and validate prognostic and predictive biomarkers to improve outcome; (2)identify therapeutic targets to inform future drug repurposing and development; (3) understand the mechanisms driving resistant/recurrent disease. I continue to work on the microenvironment in ALL and together with Kristina Kirschner (Glasgow) we will work on an MRC-funded project where our overarching goal is to probe the role of the senescent cells we have identified in sustaining and propagating the cancer cells and sustaining MRD.

Publications

Kantarjian H, Stein A, Gokbuget N, Fielding AK, Schuh AC, Ribera JM, et al. Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia. N Engl J Med. 2017;376(9):836-47.
Burt R, Dey A, Aref S, Aguiar M, Akarca A, Bailey K, et al. Activated stromal cells transfer mitochondria to rescue acute lymphoblastic leukemia cells from oxidative stress. Blood. 2019;134(17):1415-29.
Patel B, Kirkwood AA, Dey A, Marks DI, McMillan AK, Menne TF, et al. Pegylated-asparaginase during induction therapy for adult acute lymphoblastic leukaemia: toxicity data from the UKALL14 trial. Leukemia. 2017;31(1):58-64.
Mitchell RJ, Kirkwood AA, Barretta E, Clifton-Hadley L, Lawrie E, Lee S, et al. IKZF1 alterations are not associated with outcome in 498 adults with B-precursor ALL enrolled in the UKALL14 trial. Blood Adv. 2021;5(17):3322-32.
Aref S, Castleton AZ, Bailey K, Burt R, Dey A, Leongamornlert D, et al. Type 1 Interferon Responses Underlie Tumor-Selective Replication of Oncolytic Measles Virus. Mol Ther. 2020;28(4):1043-55.

Selected key positions held:

Current

President of the British Society for Haematology 2-year term from April 2020
Chair of the European Working Group on Acute Lymphoblastic Leukaemia Nov 2019- present
Founder member European Haematology Association Diversity and Equality Task force (2021 -)
Member European Haematology Association Research Committee 2021 -

Past

Chair, UK National Cancer Research Institute (NCRI) adult ALL sub-group (2009 - 2019)
Course Director European Haematology Association/American Society of Haematology Translational Research Training in Haematology 2018
Board member European School of Haematology (2017 - 2021)
Director of Research and Development Royal Free London NHS Foundation Trust 2013 - 2018

Allan Hackshaw biostatistician leads CRUK/UCL Cancer Trials Centre and has developed novel trial methodologies.

Research

The design, conduct, analysis and interpretation of clinical trials, observational studies and systematic reviews, primarily in cancer treatments and diagnosis. But I have also been a key researcher in adult and prenatal screening, and tobacco and health. This has included phase I-III trials, major cohort and case-control studies, and large real-world data studies. Specific focus has been on anti-cancer treatments for lung and thyroid cancer (and breast cancer several years ago).

High impact examples

Cancer therapies:

seminal national trial for early stage thyroid cancer which changed international clinical practice, to use low dose radioiodine and Thyrogen (HiLo).
the UK’s first ever biomarker directed treatment trial in lung cancer (ET trial).
off-patent drugs for treating lung cancer: large RCT to evaluate statins when added to chemotherapy for treating advanced small cell lung cancer (LungSTAR).
Large RCT that showed that 1 radiation fraction is just as effective for pain relief as the standard 5 fractions for treating patients with metastatic cancer spread to the spine; allowing patients to avoid unnecessary hospital visits towards the end of life (SCORAD).
The UK’s only ever national surgical trial in oral cancer and the only multicentre trial evaluating the benefits of upfront neck dissection when treating early stage neck node positive patients with oral cancer (SEND).

Cancer screening:

One of only 2 RCTs of lung cancer screening conducted in the UK (LungSEARCH); although it failed to find a more efficient screening strategy than low dose CT in all high risk people it showed clearly that people with COPD benefit in particular from screening.
Conducted the first ever systematic reviews of (i) mammography screening for breast cancer and (ii) routine breast self-examination for breast cancer.

Tobacco and health (seminal systematic reviews of):

passive smoking and lung cancer (used by the UK government to justify the ban on smoking in public places)
maternal smoking during pregnancy and birth defects
the large effects of light smoking on cardiovascular disease.

Future plans

As well as continuing to develop new clinical trials I am one of the main investigators developing TRACERx-EVO, the follow on large scale genomics study on lung cancer, with Prof Charles Swanton as the lead.
Expand projects that evaluate multicancer early detection (MCED) blood tests. This will be in collaboration with Grail Inc, as part of the UCL-sponsored SUMMIT study (~14,000 people who had low dose CT); and working with other companies to help develop a programme of studies to examine their own MCED tests.
Close collaboration with Roche, who is sponsor of a new longitudinal cancer registry WAYFIND-R (target recruitment >15,000 patients undergoing next generation sequencing for solid tumours; >25 countries). Involved in the study concept and design, and co-chair of the external academic international steering committee. This huge unique data resource will be available to academic and commercial researchers for a variety of purposes.
To expand the use of IT technology to aid clinical trial conduct and especially patient involvement. A new collaboration has started with Navio (US) to use and evaluate their mobile phone/tablet app to collect QoL data directly from trial patients and to keep them informed of trial progress. The plan is to roll this out to other cancer studies conducted by the trials centre.

Top 5 publications from 2015

Lee SM, Falzon M, Blackhall F, Spicer J, Nicolson M, Chaudhuri A, Middleton G, Ahmed S, Hicks J, Crosse B, Napier M, Singer JM, Ferry D, Lewanski C, Forster M, Rolls S, Capitanio A, Rudd R, Iles N, Ngai Y, Gandy M, Lillywhite R, Hackshaw A. Randomised prospective biomarker trial of ERCC1 for comparing platinum and non-platinum therapy, in advanced non-small cell lung cancer (ERCC1 Trial [ET]). JCO 2017; 35(4): 402-411
Jamal-Hanjani M, Wilson GA, McGranahan N, Birkbak NJ, Watkins TBK, Veeriah S, Shafi S, Johnson DH, Mitter R, Rosenthal R, Salm M, Horswell S, Escudero M, Matthews N, Rowan A, Chambers T, Moore DA, Turajlic S, Xu H, Lee SM, Forster MD, Ahmad T, Hiley CT, Abbosh C, Falzon M, Borg E, Marafioti T, Lawrence D, Hayward M, Kolvekar S, Panagiotopoulos N, Janes SM, Thakrar R, Ahmed A, Blackhall F, Summers Y, Shah R, Joseph L, Quinn AM, Crosbie PA, Naidu B, Middleton G, Langman G, Trotter S, Nicolson M, Remmen H, Kerr K, Chetty M, Gomersall L, Fennell DA, Nakas A, Rathinam S, Anand G, Khan S, Russell P, Ezhil V, Ismail B, Irvin-Sellers M, Prakash V, Lester JF, Kornaszewska M, Attanoos R, Adams H, Davies H, Dentro S, Taniere P, O'Sullivan B, Lowe HL, Hartley JA, Iles N, Bell H, Ngai Y, Shaw JA, Herrero J, Szallasi Z, Schwarz RF, Stewart A, Quezada SA, Le Quesne J, Van Loo P, Dive C, Hackshaw A, Swanton C; TRACERx Consortium. Tracking the Evolution of Non-Small-Cell Lung Cancer. NEJM. 2017;376:2109-2121
Hackshaw A, Morris JK, Boniface S, Tang JL, Milenković D. Low cigarette consumption and risk of coronary heart disease and stroke: meta-analysis of 141 cohort studies in 55 study reports.BMJ. 2018;360:j5855. doi:
Hoskin PJ, Hopkins K, Misra V, Holt T, McMenemin R, Dubois D, McKinna F, Foran B, Madhavan K, MacGregor C, Bates A, O'Rourke N, Lester JF, Sevitt T, Roos D, Dixit S, Brown G, Arnott S, Thomas SS, Forsyth S, Beare S, Reczko K, Hackshaw A, Lopes A. Effect of Single-Fraction vs Multifraction Radiotherapy on Ambulatory Status Among Patients With Spinal Canal Compression From Metastatic Cancer: The SCORAD Randomized Clinical Trial. JAMA. 2019;322(21):2084-2094.
Clark J. Dwyer D, Pinwill N, Clark P, Johnson P, Hackshaw A. The effect of clinical decision-making for starting systemic anti-cancer treatments in response to the coronavirus pandemic in England: A Retrospective Analysis. Lancet Oncol 2020; Nov 27:S1470-2045(20)30619-7

Key articles in cancer before 2015:

Mallick U, Harmer C, Yap B, Wadsley J, Clarke S, Moss L, Nicol A, Clark PM, Farnell K, McCready R, Smellie J, Franklyn J, John R, Nutting C, Newbold K, Lemon C, Gerrard G, Abdel-Hamid A, Hardman J, Macias E, Roques T, Whitaker S, Vijayan R, Alvarez P, Beare S, Forsyth S, Kadalayil L, Hackshaw A. Ablation with Low-Dose Radioiodine and Thyrotropin Alfa in Thyroid Cancer. NEJM 2012; 366:1674-1685
Hackshaw A, Roughton M, Forsyth S, Monson K, Reczko K, Sainsbury R, Baum M. Long-term benefits of 5 years of tamoxifen: 10 year follow up of a large randomised trial in women aged at least 50 years with early breast cancer. JCO 2011; 29(13):1657-63.
Tobias J, Monson K, Gupta N, MacDougall H, Glaholm J, Hutchison I, Kadalayil L, Hackshaw A. Chemo-radiotherapy for locally advanced head and neck cancer: ten-year follow up of the UK Head and Neck (UKHAN1) trial. Lancet Oncology 2009; 11: 66-74
Hackshaw A, BaumM, FornanderT, NordenskjoldB, NicolucciA, MonsonK, ForsythS, ReczkoK, JohanssonU, FohlinH, ValentiniM, SainsburyR. Long-term effectiveness of adjuvant goserelin in women with early breast cancer. JNCI 2009;101: 341-349.
Hackshaw AK, Law MR, Wald NJ. The accumulated evidence on lung cancer and environmental tobacco smoke. Br Med J 1997;315:980-88.

Key positions held:

European Commission Horizon 2020: several grant evaluation panels (rare disorders, public health, cancer, AI)
Chair of the review panel for the EU Innovative Medicines Initiative (IMI) for the haematological cancer programme (HARMONY)
Data Monitoring Boards for large/pivotal international trials (Roche)
UK National Screening Committee Adult Reference Group (expert epidemiologist)
British Thoracic Oncology Group (BTOG) Executive Steering Committee
Joint editor Journal Medical Screening (with Prof Stephen Duffy)

Maria Hawkins is Head of Radiation Oncology at UCLH with interest in proton therapy

Research theme

This theme focuses on research into state of the art radiotherapy technologies enhancing cure and reducing the incidence of treatment-related side effects. 40% of patients whose cancers are cured receive radiotherapy, and often radiation is combined with systemic treatment and surgery. Combining multiple treatment modalities can have an impact on long term toxicity burden, especially in children. Proton beam therapy (PBT) is a type of advanced radiotherapy, with the potential of more precisely delivering a targeted dose of radiation to the tumour while improving the sparing of the surrounding healthy tissues and because the dose is delivered in the tumour there is no exit dose there will be side-effects and improved quality-of-life.

High impact examples

Following research undertaken in Canada(Tse, Hawkins et al. 2008) and Oxford (Holyoake, Robinson et al. 2021) I have established the stereotactic ablative radiotherapy (SABR) service offering high precision, short courses of radiotherapy to patients with inoperable cancers (liver and pancreas) and oligometastatic disease. This has been evaluated(Chalkidou, Macmillan et al. 2021, Jin, Chalkidou et al. 2021) and it is now an NHS England commissioned service and reference arm for SABR trials.

My research in normal tissue toxicity has led to introduction of intensity modulated radiotherapy (IMRT) for anal cancer malignancies as UK standard of care in 2013 (Muirhead, Adams et al. 2014). This technique was audited nationally by the Royal College of Radiologists and we have shown reduction in toxicity (Muirhead, Drinkwater et al. 2017) (Jones, Adams et al. 2018)and improved patient reported outcomes (Gilbert, Drinkwater et al. 2020). These and radiobiological modelling (Muirhead, Partridge et al. 2015) underpin the current platform trial (PLATO) testing individualised dose in anal cancer (Gilbert, McParland et al. 2019).

Future plans

Our research aims to advance translational, and personalised medicine using artificial intelligence incorporating imaging and biological biomarkers. By rapidly accessing all relevant data available for a patient and utilising smart analysis tools we will enhance our prediction of radiation benefit or toxicity and establish specific radiation treatments to individual patients.

Radiotherapy may be made more effective at killing cancer cells by combining it with drugs. The drugs can enhance the DNA damage in tumour caused by radiation or can stimulate the immune system. We will study if combining proton therapy with immunotherapy can overcome the immune suppression caused by cancers and make the treatment effective by triggering systemic anti-tumour effects in cancers of unmet need.

Top 5 key publications

Mukherjee S, Hurt C, Radhakrishna G, Gwynne S, Bateman A, Gollins S, et al. Oxaliplatin/capecitabine or carboplatin/paclitaxel-based preoperative chemoradiation for resectable oesophageal adenocarcinoma (NeoSCOPE): Long-term results of a randomised controlled trial. Eur J Cancer. 2021;153:153-61.
Chalkidou A, Macmillan T, Grzeda MT, Peacock J, Summers J, Eddy S, et al. Stereotactic ablative body radiotherapy in patients with oligometastatic cancers: a prospective, registry-based, single-arm, observational, evaluation study. The lancet oncology. 2021;22(1):98-106.
Vivekanandan S, Landau DB, Counsell N, Warren DR, Khwanda A, Rosen SD, et al. The Impact of Cardiac Radiation Dosimetry on Survival After Radiation Therapy for Non-Small Cell Lung Cancer. Int J Radiat Oncol Biol Phys. 2017;99(1):51-60.
Sharma RA, Plummer R, Stock JK, Greenhalgh TA, Ataman O, Kelly S, et al. Clinical development of new drug-radiotherapy combinations. Nature reviews Clinical oncology. 2016;13(10):627-42.
Warren S, Partridge M, Bolsi A, Lomax AJ, Hurt C, Crosby T, et al. An Analysis of Plan Robustness for Esophageal Tumors: Comparing Volumetric Modulated Arc Therapy Plans and Spot Scanning Proton Planning. Int J Radiat Oncol Biol Phys. 2016;95(1):199-207.

Publications before 2005

Tse RV, Hawkins M, Lockwood G, Kim JJ, Cummings B, Knox J, et al. Phase I study of individualized stereotactic body radiotherapy for hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2008;26(4):657-64.
Tree AC, Khoo VS, Eeles RA, Ahmed M, Dearnaley DP, Hawkins MA, et al. Stereotactic body radiotherapy for oligometastases. The lancet oncology. 2013;14(1):e28-37

Key positions held

CRUK CoL RADNET clinical director
Member CRUK CRC committee
NCRI hepatobiliary subgroup chair
Pancreatic Cancer UK scientific advisory board member
ASTRO (American society of Radiation Oncology) Science Council member
AMMF the cholangiocarcinoma charity- medical advisor

Sam Janes is internationally leading pulmonologist developed early diagnostics of lung cancer including large population based imaging surveillance study of smokers.

Research

Sam Janes has discovered that pre-cancerous lesions in the airways are not always destined to become cancer. This observation brings with it several possibilities. Can we determine which precancerous areas are going to progress to cancer so we can deliver treatments earlier? By understanding why some lesions progress and some regress can we develop new therapies preventing lesion progression to cancer? Finally, does this knowledge enable us to potentially prevent airway cancers altogether? Over the last 15 years he has built internationally unique cohorts of patients with pre-cancerous airway lesions and followed the lesions and patients’ clinical outcomes over time. He used biopsies to map the genetic and immune landscapes of the lesions. This has allowed him to compare lesions that progress to cancer to those that harmlessly regress. He discovered a large number of genetic disturbances and can use these to accurately predict lesion progression. More recently we have also discovered a remarkable regenerative capacity of the lung: that in the right environment, highly damaged but microscopically ‘normal’ airway cells are replaced with cells undamaged by tobacco.

He has successfully delivered several clinical trials that have altered NICE guidelines and national policy on lung cancer diagnosis and CT screening (Navani et al. Lancet Resp. Med. 2015). Sam Janes leads three first in man studies including two cell and gene therapy phase 1/2 trials for lung cancer and mesothelioma based on his own pre-clinical data (TACTICAL and STATEGIC; first patients recruited June 2019; funded by MRC and INNOVATE). He also leads the first randomised controlled trial in treating pre-invasive airway lesions (EARL; funded by CRUK). Finally he leads the SUMMIT study. SUMMIT delivers CT screening to 13,000 people in London and includes data and biomarker collection as well as saving around 200 lives. SUMMIT will supply an unparalleled research legacy to UK investigators including clinical data, biomarkers and around 40,000 CT chests. All his trials are investigator lead and sponsored by UCL.

Sam will continue to develop his significant clinical cohorts to deliver data and biosamples to the UCLH laboratories while having significant clinical impact. He plans to understand the pathobiology of cancer development in more detail, documenting the clonal dynamics of precancerous lesion growth, charting genetic and epigenetic abnormalities and immunophenotypes, including antigen-T cell interactions over time and space within the lesions and their surrounding tissues. His vision from his seminal discovery documenting airway repair from tobacco damage leads to two hypotheses that will be studies. First, our current understanding of ‘field of injury’ is too simplistic; we need cellular level understanding to predict an individual’s risk of future cancer. Second, if we can understand the cellular mechanisms driving the loss of highly mutated cells over low-mutant cells in those quitting smoking, we will not only be able to potentially titre cancer risk but also open a new field of medical science manipulating this process thereby intercepting cancer prior to even pre-cancerous lesion development.

Top 5 publications

Perspectives on the treatment of Malignant Pleural Mesothelioma. Janes SM, Alrifai D and Fennell D. N Engl J Med. 2021 Sep 23;385(13):1207-1218.
Tobacco smoking and somatic mutations in human bronchial epithelium. Yoshida K, Gowers KHC, Lee-Six H, Chandrasekharan DP, Coorens T, Maughan EF, Beal K, Menzies A, Millar FR, Anderson E, Clarke SE, Pennycuick A, Thakrar RM, Butler CR, Kakiuchi N, Hirano T, Hynds RE, Stratton MR, Martincorena I, Janes SM*, Campbell PJ* (* co-corresponding authors). Nature. 2020 Feb;578(7794):266-272.
Immune surveillance in clinical regression of pre-invasive squamous cell lung cancer. Pennycuick A, Teixeira VH, AbdulJabbar K, Raza SEA, Lund T, Akarca A, Rosenthal R, Kalinke L, Chandrasekharan DP, Pipinikas CP, Lee-Six H, Hynds RE, Gowers KHC, Henry JY, Millar FR, Hagos YB, Denais C, Falzon M, Moore D, Antoniou S, Durrenberger PF, Furness A, Carroll B, Marceaux C, Asselin-Labat ML, Larson W, Betts C, Coussens LM, Thakrar RM, George J, Swanton C, Thirlwell C, Campbell PJ, Marafioti T, Yuan Y, Quezada SA, McGranahan N, and Janes SM. Cancer Discov. 2020 Jul 20:CD-19-1366.
Deciphering the genomic, epigenomic and transcriptomic landscapes of pre invasive lung cancer lesions. Teixeira VH, Pipinikas CP, Pennycuick A, Lee-Six H, Chandrasekharan D, Beane J, Morris TJ, Karpathakis A, Feber A, Breeze CE, Ntolios P, Hynds RE, Falzon M, Capitanio A, Carroll B, Durrenberger PF, Hardavella G, Brown JM, Lynch AG, Farmery H, Paul DS, Chambers RC, McGranahan N, Navani N, Thakrar RM, Swanton C, Beck S, George PJ, Spira A, Campbell PJ, Thirlwell C, Janes SM. Nat Med. 2019 Mar;25(3):517-525.
Lung cancer diagnosis and staging with endobronchial ultrasound-guided transbronchial needle aspiration compared with conventional approaches: an open-label, pragmatic, randomised controlled trial. Navani N, Nankivell M, Lawrence DR, Lock S, Makker H, Baldwin DR, Stephens RJ, Parmar MK, Spiro SG, Morris S, Janes SM. Lancet Respir Medicine 2015 Apr;3(4):282-9.

Membership of funding agency grant award panels

2021 - 24 Chair – CRUK Expert Review Panel
2017 - 24 CRUK Early Detection Panel
2018 Wellcome Investigator Award Panel Invitee
2014 - 17 CRUK Clinician Scientist Grant Committee
2012 - Roy Castle Lung Cancer Foundation Grant Committee
2010 - 13 British Lung Foundation Grant Committee

Prizes, Honours and Awards

Personal

2020 Overseas Visiting Professor Guangdong University of Technology, Guangzhou
2018 Fellow of the European Respiratory Society ‘FERS’
2010 European Respiratory Society Thoracic Oncology Award (Euro 10,000) Awarded to the under 45 researcher of the year. Barcelona 2010
2009 American Thoracic Society Researcher Award San Diego 2009
2003 British Thoracic Society Young Investigator of the Year, London 2003

National and Local Positions of leadership

Vice-Dean Research UCL
National Vice-Chair of the Lung Cancer Clinical Expert Group 2016-
National Lung Cancer Screening working group 2020 - 2022
NHS England CT screening working group
NHS England Cancer Steering Group Member (Lung Cancer) 2016-
UCLPartners London Cancer Pathway Director 2012 - 2018
British Thoracic Society Science and Research Committee Chair 2012 - 15
Chair of the British Thoracic Society National Meeting 2112 - 2015
Director of UCL Lungs for Living Centre 2012-
Head of UCL Respiratory Research Department 2015-
Respiratory Chair of the International Cellular Therapy Society 2014-
Chair of the European Respiratory Society Lung Cancer Working Group 2014-2016
UK Representative of the European Respiratory Society HERMES education initiative
Expert reviewer for Macmillan on smoking cessation 2016-
Chair Dept of Trade and Industry Medical Science meeting Brazil 2015
Grant Reviewer for MRC, CRUK, NIHR, Commonwealth Scholarships, Roy Castle, British Lung Foundation, and numerous others
Epidermal Growth Factor Receptor Best Practice Guidelines Group
Royal College of Physicians Research Committee 2012 - 2018

Book: Chief Editor Encyclopaedia of Respiratory Medicine

440 chapters; Publication date Nov 2021

Encyclopaedia of Respiratory Medicine, Second Edition explores the key processes of lung diseases and their diagnosis and management. The book dissects the molecular and cellular biology, physiology and immunology that underpin normal lung function, along with the aberrations that occur in respiratory diseases, from common disorders such as asthma and COPD to rarer lung diseases such as cystic fibrosis, interstitial lung diseases and pulmonary hypertension. Written in at a time when the globe is in the grip of respiratory pandemic, lung disease has never been so prominent in the public and political conscious.

John Kelly is urologist pioneering work in robotic surgery and directing Minimal Access Centre at UCLH; trains robotic surgeons from the UK and internationally.

Mark Linch is a medical oncologist specialising in the treatment of prostate and bladder cancer.

David Linch is a haematologist and previous director of the UCLH Biomedical Research Centre Cancer Programme. He specialises in lymphoma, and focuses on acute myeloid leukaemia.

Stephan Beck applies experimental and computational approaches, to genomics and epigenomics of phenotypic plasticity in health and disease.

Research

The Medical Genomics Group has broad interests in the genomics and epigenomics of phenotypic plasticity in health and disease. We use computational and data science approaches to study genetic and epigenetic variations and how they modulate genome function. Our research aims to advance translational, regenerative and personalised medicine. We also advocate for more open data sharing and governance and science in general.

High impact examples

Human Genome Project (HGP): I led the sequencing and analysis of the Major Histocompatibility Complex, chromosome 6, significantly contributed to the analysis of chromosomes 1, 9, 10, 13, 20 and X as well as the entire human genome. HGP has catalysed biomedical research and created the foundation for personalised medicine.
Human Epigenome Project (HEP, IHEC): I co-founded both projects. As part of HEP, I led the first methylome analysis of human chromosomes using bisulfite sequencing. As part of IHEC, I led the disease and variation parts of BLUEPRINT, the EU contribution to IHEC.
Personal Genome Project UK (PGP-UK): I introduced Open Consent and Genome Donation to the UK and obtained ethics approval to recruit 100K participants for multi-omics analysis as part of PGP-UK for which I am the founding director.
Epigenome-wide association studies (EWAS): I led the development of EWAS in 2011, contributed to over 25 EWAS and led the development of numerous analysis pipelines.
Resources: I have led/participated in a number of public resource projects: The Human Genome Project, The Human Epigenome Project, The Personal Genome Project UK, International Human Epigenome Consortium IHEC, EpiGeneSys, OncoTrack, NOCRC, IDEAL, ITFoM, BLUEPRINT, EpiTRAIN, MultipleMS, EU-STANDS4PM, TRACERx.

Future plans

In addition to continuing with on-going research, I have just applied for seed funding to the BRC Fast-Track for “OMEGA: A custom genOME GenerAtor”. Data science plays an essential role in Genomic Medicine, including the NHS Genomic Medicine Service. However, the development of the underlying algorithms is severely hampered by data access issues. OMEGA will overcome this limitation with open access reference genomes from PGP and GIAB that will be customised by machine learning approaches with quantifiable (epi)genetic variants and signatures of clinically relevant phenotypes and diseases for diverse ancestries.

Top 5 publications from 2015

Teschendorff AE, Zhu T, Breeze CE, Beck S. EPISCORE: cell type deconvolution of bulk tissue DNA methylomes from single-cell RNA-Seq data. Genome Biol. 2020 Sep 4;21(1):221.
Rosenthal R, Cadieux EL, Salgado R, Bakir MA, Moore DA, Hiley CT, Lund T, Tanić M, Reading JL, Joshi K, Henry JY, Ghorani E, Wilson GA, Birkbak NJ, Jamal-Hanjani M, Veeriah S, Szallasi Z, Loi S, Hellmann MD, Feber A, Chain B, Herrero J, Quezada SA, Demeulemeester J, Van Loo P, Beck S, McGranahan N, Swanton C; TRACERx consortium. Neoantigen-directed immune escape in lung cancer evolution. Nature. 2019 Mar;567(7749):479-485.
Frampton D, Schwenzer H, Marino G, Butcher LM, Pollara G, Kriston-Vizi J, Venturini C, Austin R, de Castro KF, Ketteler R, Chain B, Goldstein RA, Weiss RA, Beck S, Fassati A. Molecular Signatures of Regression of the Canine Transmissible Venereal Tumor. Cancer Cell. 2018 Apr 9;33(4):620-633.e6.
Stricker SH, Köferle A, Beck S. From profiles to function in epigenomics. Nat Rev Genet. 2017 Jan;18(1):51-66.
Libertini E, Heath SC, Hamoudi RA, Gut M, Ziller MJ, Herrero J, Czyz A, Ruotti V, Stunnenberg HG, Frontini M, Ouwehand WH, Meissner A, Gut IG, Beck S. Saturation analysis for whole-genome bisulfite sequencing data. Nat Biotechnol. 2016 34:691–693.

Publications before 2015

Rakyan VK, Down TA, Balding DJ, Beck S. Epigenome-wide association studies for common human diseases. Nat Rev Genet. 2011 Jul 12;12(8):529-41.
Down TA, Rakyan VK, Turner DJ, Flicek P, Li H, Kulesha E, Gräf S, Johnson N, Herrero J, Tomazou EM, Thorne NP, Bäckdahl L, Herberth M, Howe KL, Jackson DK, Miretti MM, Marioni JC, Birney E, Hubbard TJ, Durbin R, Tavaré S, Beck S. A Bayesian deconvolution strategy for immunoprecipitation-based DNA methylome analysis. Nat Biotechnol. 2008 Jul;26(7):779-85.
Eckhardt F, Lewin J, Cortese R, Rakyan VK, Attwood J, Burger M, Burton J, Cox TV, Davies R, Down TA, Haefliger C, Horton R, Howe K, Jackson DK, Kunde J, Koenig C, Liddle J, Niblett D, Otto T, Pettett R, Seemann S, Thompson C, West T, Rogers J, Olek A, Berlin K, Beck S. DNA methylation profiling of human chromosomes 6, 20 and 22. Nat Genet. 2006 Dec;38(12):1378-85.
Mungall, A.J. S.A. Palmer S.K. Sims C.A. Edwards J.L. Ashurst L. Wilming M.C. Jones R. Horton S.E. Hunt C.E. Scott J.G. Gilbert M.E. Clamp G. Bethel S. Milne R. Ainscough J.P. Almeida K.D. Ambrose T.D. Andrews R.I. Ashwell A.K. Babbage C.L. Bagguley J. Bailey R. Banerjee D.J. Barker K.F. Barlow K. Bates D.M. Beare H. Beasley O. Beasley C.P. Bird S. Blakey S. Bray-Allen J. Brook A.J. Brown J.Y. Brown D.C. Burford W. Burrill J. Burton C. Carder N.P. Carter J.C. Chapman S.Y. Clark G. Clark C.M. Clee S. Clegg V. Cobley R.E. Collier J.E. Collins L.K. Colman N.R. Corby G.J. Coville K.M. Culley P. Dhami J. Davies M. Dunn M.E. Earthrowl A.E. Ellington K.A. Evans L. Faulkner M.D. Francis A. Frankish J. Frankland L. French P. Garner J. Garnett M.J. Ghori L.M. Gilby C.J. Gillson R.J. Glithero D.V. Grafham M. Grant S. Gribble C. Griffiths M. Griffiths R. Hall K.S. Halls S. Hammond J.L. Harley E.A. Hart P.D. Heath R. Heathcott S.J. Holmes P.J. Howden K.L. Howe G.R. Howell E. Huckle S.J. Humphray M.D. Humphries A.R. Hunt C.M. Johnson A.A. Joy M. Kay S.J. Keenan A.M. Kimberley A. King G.K. Laird C. Langford S. Lawlor D.A. Leongamornlert M. Leversha C.R. Lloyd D.M. Lloyd J.E. Loveland J. Lovell S. Martin M. Mashreghi-Mohammadi G.L. Maslen L. Matthews O.T. McCann S.J. McLaren K. McLay A. McMurray M.J. Moore J.C. Mullikin D. Niblett T. Nickerson K.L. Novik K. Oliver E.K. Overton-Larty A. Parker R. Patel A.V. Pearce A.I. Peck B. Phillimore S. Phillips R.W. Plumb K.M. Porter Y. Ramsey S.A. Ranby C.M. Rice M.T. Ross S.M. Searle H.K. Sehra E. Sheridan C.D. Skuce S. Smith M. Smith L. Spraggon S.L. Squares C.A. Steward N. Sycamore G. Tamlyn-Hall J. Tester A.J. Theaker D.W. Thomas A. Thorpe A. Tracey A. Tromans B. Tubby M. Wall J.M. Wallis A.P. West S.S. White S.L. Whitehead H. Whittaker A. Wild D.J. Willey T.E. Wilmer J.M. Wood P.W. Wray J.C. Wyatt L. Young R.M. Younger D.R. Bentley A. Coulson R. Durbin T. Hubbard J.E. Sulston I. Dunham J. Rogers and S. Beck. The DNA sequence and analysis of human chromosome 6. Nature 2003 425: 805-811.
The International Human Genome Sequencing Consortium. Initial sequencing and analysis of the human genome. Nature 2001 409: 860-921.
The MHC Sequencing Consortium. Complete sequence and gene map of a human major histocompatibility complex. Nature 1999 401: 921-923.
Beck, S. and B.G. Barrell. Human cytomegalovirus encodes a glycoprotein homologous to MHC class-I antigens. Nature 1988 331: 269-272.

Other information

Developed and implemented a GDPR-compliant harmonised Data Access Agreement

https://www.eu-stands4pm.eu/data_access

Key positions held

Professor of Medical Genomics
UCL Cancer Institute
UCL Institute of Digital Health
UCL Institute for Precision Medicine
Director, Personal Genome Project UK

Paula Lorgelly investigates health economic implications of new technologies in cancer focusing on personalised cancer therapy.

Economics of Implementation

The benefits to patients and the wider healthcare system that new cancer technologies can deliver won’t be realised unless these therapies are approved for use and implemented into the healthcare system. There are a number of methodological and practical developments in health economics that can help inform the adoption and implementation of new therapies. For example, a methodological development that warrants investigation is the idea to broaden the outcomes of interest, identifying other value elements, not just health related quality of life as used to calculate quality adjusted life years (QALYs).

These new elements of value could be important to patients (reduced uncertainty, hope), but also to science and discovery (scientific spillovers) and commissioners and decision makers (equity). Health economics within the BRC is important for ensuring that the evidence needed for implementation is collected, analysed and presented to aid adoption. Implementation needs be seen as the end game, without research focusing on this the BRC will not deliver maximum impact.

High impact examples

Over the last 5 years I have been funded by Cancer Research UK to explore innovations in payment models, including the use of risk sharing agreements, indication based pricing and outcome based pricing in the NHS.

Cole, A., Cubi-Molla, P., Pollard, J., Sim, D., Sullivan, R., Sussex, J., & Lorgelly, P. (2019). Making outcome-based payment a reality in the NHS: Phase 1. Cancer Research UK.
Cole, A., Cubi-Molla, P., Elliott, R., Feast, A., Hocking, L., Lorgelly, P., Payne, K., Peek, N., Sim, D., Sussex, J., Zhang, K and Steuten, L. (2021) Making Outcome-Based Payment a Reality in the NHS. Phase 2: Practical Considerations. Cancer Research UK.

Future plans

Health economists will be actively engaged with BRC collaborators to (a) assess the value to new technologies using the current cost effectiveness paradigm, cost per QALY gained, by analysing trial data and undertaking extrapolations to model the lifetime cost effectiveness; (b) assess the value of research, in the form of early cost effectiveness analyses to determine whether the new information generated through proposed research reduces the uncertainty of making a decision and whether the expected payoffs from this exceed the costs of undertaking the research; (c) challenge the narrow view that assesses the value of technologies using QALYs only and determining what other elements of health and healthcare patients value, and how BRC research projects can collect this in order to operationalise what will be a challenge to the current health technology assessment paradigm; (d) working with decision makers and commissioners to understand what evidence they need and how they want it presented in order to inform adoption and implementation decisions.

Top 5 publications

Lorgelly PK, Adler A. Impact of a global pandemic on health technology assessment. Applied health economics and health policy. 2020 Jun;18(3):339-43.
Christensen H, Al-Janabi H, Levy P, Postma MJ, Bloom DE, Landa P, Damm O, Salisbury DM, Diez-Domingo J, Towse AK, Lorgelly PK. Economic evaluation of meningococcal vaccines: considerations for the future. The European Journal of Health Economics. 2020 Mar;21(2):297-309.
Lorgelly PK, Neri M. Survivorship burden for individuals, households and society: estimates and methodology. Journal of cancer policy. 2018 May 1;15:113-7.
Lorgelly PK, Doble B, Rowen D, Brazier J. Condition-specific or generic preference-based measures in oncology? A comparison of the EORTC-8D and the EQ-5D-3L. Quality of Life Research. 2017 May;26(5):1163-76.
Devlin NJ, Lorgelly PK. QALYs as a measure of value in cancer. Journal of Cancer Policy. 2017 Mar 1;11:19-25.

Key positions

PGfAR NIHR Panel member
National Organiser of the Health Economists’ Study Group
NIHR ARC North Thames Health Economics and Data Theme Leader

Marc Mansour is a haemato-oncologist discovered role of noncoding mutations in cancer and therapeutic potential of epigenetic modification in leukaemia.

Research

Our laboratory focuses on T-cell acute lymphoblastic leukaemia (T-ALL) and AML, spanning both basic and translational science. Our current research programme is underpinned by three key areas:

Mechanisms of oncogene activation: We discovered that somatic mutations in non-coding sites can create de novo enhancers (Mansour et al. Science 2014). We are exploring how mutations nucleate enhancers and alter higher order chromatin structure. Furthermore, we propose that identifying non-coding driver mutations will be a route to discovery of previously unappreciated therapeutic targets.
Synthetic lethality to target tumour suppressor genes: Synthetic lethality, whereby loss of one gene leads to a dependency on another gene or pathway, offers a means of targeting tumours deficient in a tumour suppressor while sparing normal cells. We use genome-wide screens to discover novel synthetic lethal interactions in T-ALL and AML.
Chemotherapy resistance: Approximately three times as many T-ALL patients fail to achieve remission with induction chemotherapy compared to those with B-ALL (O’Connor et al JCO 2017), though the clinical phenomenon remains unexplained. We have established a CRUK funded study to analyse all cases of relapsed paediatric ALL nationwide for detailed genomic analyses and drug response profiling.

High impact examples

Non-coding driver mutations – we were the first to show that oncogenes can be activated through somatic mutations in non-coding sites that create de novo enhancers (Mansour et al Science 2014). We have been able to identify non-coding driver mutations at other key oncogenes across multiple cancer types (Li et al. Leukemia 2017; Rahman et al. Blood 2017; Abraham et al. Nature Communications 2017). This dataset has now been developed into a user-friendly browsable interactive database available free to the research community (http://enhancer-indel.cam-su.org)
Identification of MYB as a member of the TAL1-LMO2 complex in T-ALL. We have shown a novel interaction between MYB and TAL1 in T-ALL (Mansour et al Science 2014). Therapeutic targeting of this complex is the basis of a CRUK PFA 2021-2027.
Synthetic lethal interaction between CHK1 and EZH2 mutations in T-ALL: We have recently discovered that T-ALLs harbouring loss-of-function mutations in EZH2 become dependent on CHK1, establishing a new role for clinically available CHK1 inhibitors in this aggressive disease subset (Leon et al. Cancer Discovery 2020).
NOTCH-1 mutations in T-ALL pathogenesis - we demonstrated that NOTCH1 mutations are often acquired as late secondary events during oncogenesis (Mansour et al. Clin Cancer Research 2007; Howe et al. JCI, 2006; >1000 citations). The clinical implication of this is clonal selection of NOTCH1 wild-type leukaemic clones during NOTCH-directed therapy, one of several reasons why NOTCH inhibitors have failed to make an impact clinically in T-ALL.

Future plans

Establish a national pipeline for drug response profiling and genomics for all relapsed acute leukaemia cases (through a CRUK Children’s Young Persons Innovation Award)
Establish a comprehensive digito-biological biobank for primary leukaemia and PDX samples at GOSH
Identify novel synthetic lethal interactors for other leukaemia tumour suppressor genes such as TET2 and DNMT3A
Identify druggable regions of MYB-TAL1 and MYC (CRUK PFA and CRUK Pioneer Award)
Commence first-in-human study of novel immunotherapy approach for T-ALL

Top 5 publications form 2015

Leon, T. E., Rapoz-D'Silva, T., Bertoli, C., Rahman, S., Magnussen, M., Philip, B., Farah, N., Richardson, S. E., Ahrabi, S., Guerra-Assuncao, J. A., Gupta, R., Nacheva, E. P., Henderson, S., Herrero, J., Linch, D. C., de Bruin, R. A. M. & Mansour, M. R. EZH2-Deficient T-cell Acute Lymphoblastic Leukemia Is Sensitized to CHK1 Inhibition through Enhanced Replication Stress. Cancer Discov 10, 998-1017, doi:10.1158/2159-8290.CD-19-0789 (2020).
Mansour, M. R.*, He, S., Li, Z., Lobbardi, R., Abraham, B. J., Hug, C., Rahman, S., Leon, T. E., Kuang, Y. Y., Zimmerman, M. W., Blonquist, T., Gjini, E., Gutierrez, A., Tang, Q., Garcia-Perez, L., Pike-Overzet, K., Anders, L., Berezovskaya, A., Zhou, Y., Zon, L. I., Neuberg, D., Fielding, A. K., Staal, F. J. T., Langenau, D. M., Sanda, T., Young, R. A. & Look, A. T*. JDP2: An oncogenic bZIP transcription factor in T cell acute lymphoblastic leukemia. The Journal of experimental medicine 215, 1929-1945, doi:10.1084/jem.20170484 (2018). *co-corresponding authors
Rahman, S., Magnussen, M., Leon, T. E., Farah, N., Li, Z., Abraham, B. J., Alapi, K. Z., Mitchell, R. J., Naughton, T., Fielding, A. K., Pizzey, A., Bustraan, S., Allen, C., Popa, T., Pike-Overzet, K., Garcia-Perez, L., Gale, R. E., Linch, D. C., Staal, F. J., Young, R. A., Look, A. T. & Mansour, M. R. Activation of the LMO2 oncogene through a somatically acquired neomorphic promoter in T-cell acute lymphoblastic leukemia. Blood, doi:10.1182/blood-2016-09-742148 (2017).
Abraham, B. J., Hnisz, D., Weintraub, A. S., Kwiatkowski, N., Li, C. H., Li, Z., Weichert-Leahey, N., Rahman, S., Liu, Y., Etchin, J., Li, B., Shen, S., Lee, T. I., Zhang, J., Look, A. T. *, Mansour, M. R.* & Young, R. A*. Small genomic insertions form enhancers that misregulate oncogenes. Nature communications 8, 14385, doi:10.1038/ncomms14385 (2017). *co-corresponding authors
Mansour, M. R., Abraham, B. J., Anders, L., Berezovskaya, A., Gutierrez, A., Durbin, A. D., Etchin, J., Lawton, L., Sallan, S. E., Silverman, L. B., Loh, M. L., Hunger, S. P., Sanda, T., Young, R. A. & Look, A. T. Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element. Science 346, 1373-1377, doi:10.1126/science.1259037 (2014).

Other information

Two patent applications submitted Sept 2021 for novel immunotherapy approaches to T-ALL.

Invited talks last 2 years:

2021 American Society of Hematology (ASH) Scientific Session: ‘Non-coding driver mutations in T-ALL’
2021 EHA Educational Session: ‘Genetic Landscape of T-ALL’
2021 Erasmus Haematology Series: ‘Epigenetic vulnerabilities of T-ALL’
2019 FASEB, Colorado, USA. ‘Synthetic lethality approach to targeting EZH2 mutant T-ALL’.

Key positions held

June 2021 onward Great Ormond Street Children’s Charity Professor of Haemato-Oncology, GOS ICH
Feb 2018-May 2021 Associate Professor, UCL Cancer Institute, London.
2015-present Honorary Consultant Haematologist, UCLH. Clinically active, acute leukaemia service.
2014-2019 Bennett Senior Fellow (Bloodwise); UCL Cancer Institute, London
2017-2018 Biomedical Research Centre Senior Clinical Researcher
2012-2014 Instructor, Department of Pediatrics, Harvard Medical School, Boston, USA
2009-2014 Post-doctoral research fellow, Dana-Farber Cancer Institute/Harvard Medical School, Boston
2002-2009 Clinical Haematology Specialist Registrar, University College London

Roles

2021-present GOSHCC Cancer Centre strategy leadership committee
2017-present Crick-CRUK Academic Steering Committee member
2019-present Therapeutic Innovation Network Committee Member, UCL
2018-present Haematology Clinical Research Fellowship co-ordinator, UCL Cancer Institute
2018-present London Leukaemia Club co-ordinator/chair

Teresa Marafioti is a renowned lymphoma pathologist introduced multiparameter staining for immune microenvironment in lung and prostate cancer, lymphoma.

Research

I am a professor of Haematopathology at UCL and a consultant Haematopathologist at UCLH. I lead a small research team at UCL Cancer Institute that established collaborations across different research groups within UCL and across UK, Europe and America.

My research career began in 1993 in Berlin under the supervision of Prof. H. Stein, one of the stalwarts of Haematopathology, as a clinical research fellow focussed on the pathogenesis of Hodgkin Lymphoma (HL). Using cutting edge technology at the time – single cell microdissection and sequencing – we provided definitive evidence for identifying the lineage of neoplastic cells in a particular form of Hodgkin Lymphoma. This work was published in the New England Journal of Medicine in 1997 and I was first author.

In February 2000, I moved to the University of Oxford to join the team of Prof D. Y. Mason and I focused on the analysis of mono and polyclonal antibodies against surface and intracellular proteins to investigate normal lymphocyte biology and lymphoma diagnosis. This led to the discovery of unique biomarkers such as PD-1, ICOS, and CD2AP that helped in reclassifying specific lymphoma entities. They are now in routine diagnostic use and have been included in the 4^th edition of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 2017.

Since January 2010 my work at UCLH has been funded jointly by the NHS Trust and UCL/UCLH BRC with protected research sessions that enable a 50:50 split between academic/research and diagnostic work.

I have continued my research in haemato-oncology and extended it to characterisation of lymphocyte anti-tumour cells in collaboration with the ongoing immunotherapy programmes at UCL/UCLH and external groups.

In 2015, I co-authored the guidelines on investigation and management of Nodular Lymphocyte Predominant Hodgkin Lymphoma, the first such guideline published by the British Committee for Standards in Haematology (BCSH) on this topic.

In July 2018 I received from UCL the academic promotion to Full-time Professor of Haematopathology.

In August 2021 I have accepted to be co-author of the chapter of Follicular Lymphoma (in situ, classical and paediatric subtypes) of the 5^th edition of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.

High impact examples

Below are details of my research streams and some specific examples of identified biomarkers:

Identification of Novel Markers for Lymphoma Diagnostics.
1. a. Stathmin (STMN1), a novel diagnostic marker for follicular lymphoma subgroups with an “atypical” immunophenotypic and molecular profile. STMN1 is of potential relevance for therapeutic clinical trials.This article published in J of Pathology received the 2013 Roger Cotton Prize;
2. b. BRAF (V600E), a useful diagnostic and therapeutic target for subsets of transformed chronic lymphocytic leukaemia (Richter’s Syndrome) (Br J Haematol 2015);
3. c. Granulysin, a diagnostic marker for NK/T cell malignancies (Virchows Archiv 2019);
4. d. FOXP-1, diagnostically relevant to distinguish paediatric follicular lymphoma from benign follicular hyperplasia (Virchows Archiv 2019);
Development of Novel Technologies for the Study of Lymphocyte Biology and Tissue Diagnostics
1. a. I have pioneered the development of multiplex immunostaining (MIS) to detect up to 7 different antigens in tissue samples. This is of diagnostic value in difficult to define lymphomatous entities and in defining the T-cell antitumour response in cancerous tissues. Recently, I have also modified existing techniques to enable multispectral multiplex immunofluorescence using the VECTRA platform. This allows quantitative assessment of multiple, cell surface and intracellular, antigens to detect potential mechanisms of tumour immune-escape. This technique has been applied to three large clinical studies on solid tumours and also Burkitt (Infectious Agents and Cancer 15; 2020), Follicular lymphoma and classical Hodgkin lymphoma cases (data in progress).
2. b. I have established techniques for the identification of specific RNAs cancer biomarkers when the protein is not adequately expressed or antibodies to that protein are not available (Venkatesan S et al Cancer Discovery 2021). This has proved to be useful for the detection of minimal residual disease in acute myeloid leukaemia (unpublished data) and in breast cancer where the HER2 protein expression may be lost but the RNA is still present.
Studies of the anti-tumour T-cell response in cancerous tissues
1. Capitalising on my knowledge of lymphocyte biology and my technical expertise to identify lymphocyte subsets, I have developed collaborations with the immune-therapy teams in the UCL Cancer Institute, CRICK and Imperial College London, who work on checkpoint inhibition, tumour neo-antigens and CAR T-cell therapies. This has been particularly productive for publications in leading scientific journals such as Science (2016), Lancet (2017), and Annals of Oncology (2018).
Clinical Trials co-PI
1. The established experience in the field of novel biomarkers and techniques has allowed active involvement in clinical trials at UCLH. Examples of those are:
  1. a. AUTO-4, a clinical trial (a CAR T cell treatment targeting TRBC1 in patients with relapsed or refractory TRBC1 positive selected T-Non-Hodgkin Lymphoma) funded by Autolus Ltd. In the trial, I worked as PI Pathologist and my Lab was responsible for the immunohistochemistry diagnostic assay for staining of JOV-1 antibody wich recognizes an epitope of TRBC1 protein.
  2. b. Neptunes, a clinical trial in Nivolumab and ipilimumab treatment in prostate cancer with an immunogenic signature (NEPTUNES). I am lead for the predictive biomarkers analysis of panels of T cell molecules detected by using multiplex immunostaining.

Future research plans

I intend to continue research in the areas outlined above to be able to contribute to the understanding of lymphocyte biology and pathogenesis of lymphoma with a view to develop further targeted biomarkers for lymphoma.

Building on other previous published work, I want:

to expand the understanding of lymphoma biology (planned study include follicular lymphoma, marginal zone lymphoma, diffuse large B cell lymphoma and Hodgkin lymphoma) as well as to study the role of lymphocytes and immune cell in the tumour microenvironment of solid tumours (planned studies include clinical trials cases of ovarian cancer, hepatobiliary carcinoma, prostate and bladder cancers) by using multiplex labelling technologies.
to validate the use of quantitative immunofluorescence compared to immunohistochemistry with the hope to combine these with RNA detection in the same section to provide semi-quantitative analysis as well as detailed gene changes in specific cell populations
to developed RNAscope and ISH based technique to detect TCRs mRNA in tissue sections and combine it with immunohistochemistry to study T cell clonality and specific type of TCRs in solid tumours
to complete a recently developed web-page that provides to the scientific arena educational information regarding immunohistochemistry-based assays, antibody characterisation in human and animal tissue samples and established antibody panels for multiplex-immunofluorescence.

Other information

The professional portfolio I have acquired allows to continue network academia and pharma, to maintain collaborative clinical-pathological studies and develop new ones.

I publicise my research activity internationally, being regularly invited to present at scientific conferences and meetings as well as I give talks via media coverage. Examples of the latter are the following events: May 2020 – La giornata della ricerca italiana nel mondo - Ambasciata Italiana a Londra, UK; June 2016 - Talk Show about my research engagement for cancer at the broadcasted event: “Roche per la Ricerca” - Rome, Italy; December 2016 - Video broadcast for Bristol-Myers Squibb Pharmaceutical regarding the utility of PD-L1 immunostaining in solid tumours - UCL, London, UK.

I am academic supervisor of PhD students as well as of iBsc students. I act as External and Internal Examiner of MD and PhD Students.

In February 2021 I received the honour of “Cavaliere dell’Ordine della Stella d’Italia” by the Presidency of the Italian Republic (https://www.quirinale.it/onorificenze/insigniti/363400).

I am director of the David Y Mason Foundation that promotes the DY Mason Award to foster the interest of young researchers for Haematopathology. The Award is associated to the European Association for Haematopathology and provides awards every 2 years at a dedicated session of the meeting. The leadership role I have by representing the DYM Foundation allows active participation in the selection of candidates.

Furthermore, the David Y Mason Foundation sponsors one of the young researchers winner of the “Italia Made Me 2019”. The Price is supported by the Italian Embassy of London, UK

My professional interests are: Haematopathology, Immunology, Immunohistochemistry, Digital Pathology, Molecular Pathology, Clinical Haematology and Oncology.

I speak fluently beyond English, Italian, German, French and Spanish.

Top 5 publications

Maciocia, PM, Wawrzyniecka, PA, Philip, B, Ricciardelli, I, Akarca, AU, Onuoha SC, Legut M, Cole DK, Sewell AK, Gritti G, Somja, J, Piris MA, Peggs KS, Linch DC, Marafioti T, Pule MA. Targeting T-cell receptor β-constant region for immunotherapy of T-cell malignancies. Nature medicine. 2017; 23, pages1416–1423. Available from: doi:10.1038/nm.4444.
Ghorani, E, Kaur B, Fisher RA, Short D, Joneborg U, Carlson JW, Akarca AU, Marafioti T, Quezada SA, Sarwar N, Seckl MJ. Pembrolizumab is effective for drug-resistant gestational trophoblastic neoplasia. The Lancet. 2017; 390, (10110) p2343–2345. Available from: doi:10.1016/S0140-6736(17)32894-5.
Schmidt, J, Gong, S, Marafioti, T, Mankel, B, Gonzalez-Farre, B, Balagué, O, Mozos, A, Cabeçadas, J, van der Walt, J, Hoehn, D, Rosenwald, A, Ott, G, Dojcinov, S, Egan, C, Nadeu, F., Ramis-Zaldívar, J.E, Clot, G., Bárcena, C, Pérez-Alonso, V, Endris, V, Penzel, R, Lome-Maldonado, C, Bonzheim, I, Fend F, Campo, E, Jaffe, ES, Salaverria, I, Quintanilla-Martinez, L. (2016). Genome-wide analysis of pediatric-type follicular lymphoma reveals low genetic complexity and recurrent alterations of TNFRSF14 gene. Blood, 128 (8), 1101-1111. doi:10.1182/blood-2016-03-703819
Marafioti, T, Copie-Bergman, C., Calaminici, M., Paterson, J.C., Liu, H., Baia, M., Ramsay A.D, Agostinelli C, Briere J, Clear, A., Du M.Q., Piccaluga, PP., Masir N., Nacheva, EP., Sujobert, P., Shanmugam, K., Grogan, T.M., Brooks, S., Khwaja A., Ardeshna, K., Townsend, W., Pileri, S.A., Haioun, C., Linch, D., Gribben J., Gaulard, P., Isaacson, PG. (2013). Another look at follicular lymphoma: immunophenotypic and molecular analyses identify distinct follicular lymphoma subgroups. Histopathology, 62(6):860-75. doi: 10.1111/his.12076.
Marafioti T, Hummel M, Anagnostopoulos I, Foss HD, Falini B, Delsol G, Isaacson PG, Stein H. Origin of nodular lymphocyte-predominant Hodgkin's disease from a clonal expansion of highly mutated germinal-center B cells. New England Journal of Medicine. 1997; 337 (7), 453-458. Available from: doi: 10.1056/NEJM199708143370703.

My citations metrics as it appears in three freely accessible web based bibliographic databases are: a) Google Scholar: Citations: 17534, h-index: 55, i10-index: 137; b) Scopus: Citations: 12852; h-index: 50 and c) RESEARCHERID: Citations: 1007; h-index:43.

Key positions held

April 2019. Member of the Scientific Council of the Italian Embassy in London.
July 2018. UCL Senior Academic Promotion 2018: Professor of Haematopathology.
November 2017 – present. Honorary Visiting Professor at the Institute of Pathology, University of Siena, Italy.
February 2016. Lead Haematopathology Service, Department of Cellular Pathology, University College Hospital, London, UK.
January 2015. Consultant Haematopathologist for Haematogenix Laboratory Services, Chicago IL, US and Manchester, UK.
January 2014. National Scientific Habilitation as Professor in Pathology by the Italian Ministry of University and Research.
January 2010-present. Consultant Histopathologist, Department of Cellular Pathology, University College Hospital, London, UK.
January 2010. Reader in Haematopathology, University College London, London, UK.
January 2010-January 2011. Visiting Professor Institute of Pathology, University of Creteil, Paris, France.
January 2010- December 2010. Visiting Professor Dunn School of Pathology, University of Oxford, UK.
August 2008. Reader in Haematopathology, University of Oxford, UK.
February 2004-January 2010. Clinical Lecturer at the LRF Immunodiagnostics Unit, Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, University of Oxford, UK.
July 2001-December 2009. Honorary Staff Grade, in Histopathology (Haematopathology) at the Cellular Pathology, John Radcliffe Hospitals NHS Trust, Oxford, UK.
July 2000-2007. Contract Professor at the Post-graduated Medical School of Oncology of Bologna University, Italy.
March 2000-2004. Visiting Pathologist at the LRF Immunodiagnostics Unit, Nuffield Department of Clinical Laboratory Sciences, John Radcliffe Hospital, University of Oxford, UK.
January 1993-February 2000. Clinical Lecturer at the Institute of Pathology, Free University of Berlin, Germany.

Karl Peggs is a haemato-oncologist and clinical lead for complex immunotherapy trials. Chief investigator for cell-based therapies including CAR-T. Cofounder of Achilles Therapeutics. Resigned from UCL.

Martin Pule is haemato-oncologist and scientist making major contribution to design of CAR-T therapies. Holder of x patents and Founder of Autolus Ltd.

Sergio Quezada is lead immunotherapy scientist focused on identifying immunological checkpoints and biology of tumour infiltrating lymphocytes. Cofounder of Achilles Therapeutics.

Claire Roddie is a haematologist specialising in CAR-T cell manufacture for cancer therapy.

Gary Royle is Head of Medical Physics and Biomedical Engineering at UCL with focus on proton therapy and use of AI in radiotherapy planning and trials.

Charles Swanton FRS, Chief Clinician Cancer Research UK, pioneering lung cancer oncologist. His group has identified the genetic landscape and key evolutionary routes in lung cancer. With focus on cancer neoantigens. Cofounder of Achilles Therapeutics.

Research

Charles Swanton has a long-standing interest in the application of molecular biology to cancer research with clinical impact. He leads the TRACERx cancer evolution program which led to the identification of the importance of cancer clonal neoantigens as targets for immune-therapy (Mcgranahan et al Science 2016; Litchfield et al Cell 2021). Trials of adoptive T cell therapies are in progress targeting clonal neoantigens are in progress in melanoma and NSCLC.

Through TRACERx and evolutionary approaches we have established that genome doubling is a transformative event during tumour evolution driving karytopye diversity (Dewhurst et al. 2014 Cancer Discovery) and selection (Watkins et al Nature 2020), mitigating the loss of essential genes during tumour evolution (Lopez et al 2020 Nat Genet). We have found that chromosomal instability drives ongoing selection (Watkins et al Nature 2020), immune evasion through loss of HLA (McGranahan et al. Cell 2017), clonal neoantigen loss (Rosenthal et al Nature 2019) and is associated with poor clinical outcome (Jamal-Hanjani NEJM 2017) and metastatic dissemination (Turajlic et al 2018 Cell (a); Turajlic et al. 2018 Cell(b)). Finally, through our evolutionary TRACERx program we have defined a clonally expressed biomarker of lung cancer survival (Biswas et al Nature Medicine 2020) and established phylogenetic biomarker approaches (Abbosh et al Nature 2017), with FDA breakthrough device designation, to track minimal residual disease in early-stage disease that promises to transform drug development in early-stage cancers.

High Impact

Swanton has demonstrated branching evolution in human solid tumours and characterised the prevalence and impact of cancer cell-to-cell variation (intratumour heterogeneity). He has demonstrated that chromosomal instability (CIN) promotes selection and poor clinical outcome through multiple mechanisms: the initiation of multidrug resistance; increased tumour metastases arising from selection of high-risk DNA copy number events and through HLA loss of heterozygosity and immune escape including loss of clonal neoantigens. Swanton's work revealed that whole genome duplications are transformative in tumour evolution, permitting propagation of aneuploid clones driving further diversity and are selected to mitigate the accumulation of deleterious mutations in essential cancer genes.

Swanton has revealed how cell-to-cell variation is manifested in human cancers. He has shown that DNA replication stress is a driver of CIN. His work has shown the APOBEC cytidine deaminase drives single nucleotide variation later in tumour evolution and results from DNA replication stress in an ATM/ATR/CHK1 dependent manner. He has proven that a “just-right” threshold of CIN and diversity exists in tumours, demonstrated how adaptation may occur to this threshold through APC/C mutations by lowering chromosome mis-segregation rates, and showed how BCL9L dysfunction promotes chromosome segregation error tolerance in colorectal cancer.

His work has revealed the central role played by cancer clonal mutations encoding neoantigens, present in every tumour cell, in immune surveillance, that can be used to predict checkpoint inhibitor response validated in his recent large study of >1000 patients across multiple tumour types, and the importance of clonal frameshift neoantigens in immune control. His TRACERx work has revealed how tumours evolve to escape immune predation through clonal neoantigen loss due to CIN, neoantigen transcriptional repression due to promoter methylation and allele-specific HLA loss preventing neoantigen presentation, permitting branched evolution in 40% of lung cancers.

Swanton has translated his cancer evolution work into direct clinical impact. He discovered that tumour sampling bias, with distinct driver events at distinct anatomical sites, presents a challenge to precision oncology. He has created a clinical prognostic mRNA biomarker accounting for intratumour heterogeneity, that outperforms conventional tools to guide chemotherapy use in early lung cancer. Swanton has shown how deterministic evolutionary features can distinguish “born-to-be-bad” tumours that disseminate widely to metastatic sites early from more indolent cancers. His finding that the same gene, protein complex or pathway can be disrupted in distinct tumour subclones suggests that cancer evolution is constrained and predictable. He has developed cancer evolutionary diagnostic tools now in clinical use (FDA Breakthrough Devices 2019/2020 with Natera and Archer diagnostics) tracking minimal residual disease and branching evolution of drug resistant subclones that were recently shown to identify patients deriving overall survival benefit from checkpoint inhibitor therapy after surgery. His work is changing cancer drug development and the clinical trial landscape, enabling selection of only those patients destined to relapse for escalation of drug therapy following surgical resection, for curative therapy. Finally, Swanton has found multiple cancer cytotoxic CD8+ T cell clones that recognise distinct clonal neoantigens leading to evolutionary clinical trials of T cell therapies to limit drug resistance in lung cancer and melanoma.

Future plans

Over the next 5 years, through analysis of TRACERx/PEACE datasets we will:

Resolve cancer evolution through whole exome sequencing and in selected cases, deep whole genome sequencing to explore structural variation over time, extrachromosomal DNA evolution and the role of the non-coding genome in cancer evolution
through support requested in this application, instigate an analysis of the immune microenvironment at single cell spatial resolution
increase our understanding of how and when genome instability processes are initiated in tumour evolution and their impact on immune escape and metastatic dissemination.
clinically validate and optimise minimal residual disease and clonal phylogenetic tracking technologies
Define biological processes between tumour and host that initiate cancer cachexia (not discussed in this application).

Through the TRACERx program, we will:

distinguish metastasis competent from incompetent subclones in the primary tumour, understand the evolutionary histories and relationships of metastases and determine the timing of subclonal driver events and their role in cancer cell fitness and dissemination.
address whether evolutionary trajectories in lung cancer are deterministic as we found in renal cancer, and whether they enable the forecasting of clinical outcome.
investigate the mechanistic basis for the initiation and impact of chromosomal instability (CIN)- a pattern of genome instability that we have found to be pervasive and determines survival outcome.
Through whole genome sequencing analysis in tumours from TRACERx we will attempt to understand the origins and impact of extra-chromosomal DNA evolution.
endeavour to understand how genome doubling events are initiated and tolerated, that us and others have found drive CIN, mitigating an evolutionary “rachet-like” phenomenon resulting from excessive loss of chromosomes encoding genes essential for cell survival.
advance our understanding of the mechanistic basis for the initiation and impact of APOBEC mutational processes that we have found are enriched in cancer subclones.
examine how DNA replication stress triggers APOBEC activity and through animal experiments, whether subclonal APOBEC mutagenesis drives immune exhaustion and helps precipitate metastatic dissemination.
Continue to investigate immune evasion mechanisms in NSCLC selected in subclones of the primary tumour that may be required to support the metastatic transition.
to identify tumour microenvironmental constraints to subclonal cancer evolution and mechanisms of immune escape, immune checkpoint inhibitor and drug. Through in-depth imaging characterisation of the extrinsic tumour microenvironment and cancer cell intrinsic immune evasion mechanisms derived from tumour genomics analysis,
address the extent to which metastatic competent subclones display “immune-privileged” features.
determine whether lymphatic metastases found at primary resection seed distant metastases. We will address whether subclones seeding NSCLC metastases (>400 metastases sampled 12/2020) display organ specific features or attract distinct tumour microenvironments and the role distinct cancer cell intrinsic genome instability processes may play in this process.
Through detailed clinical case report forms, assess the impact of adjuvant cytotoxic therapy and radiotherapy on genome stability and mutational processes.
address the degree to which the evolution of cancer subclones conform to neutrality or selection.
generate mouse lung cancer models that more faithfully replicate genome instability processes present in human tumours in order to functionally probe the relationships between an evolving tumour, genome instability processes and the immune microenvironment.
conduct clinical trials to test our laboratory advances in the clinical setting with a focus on A) diagnostic minimal residual disease (MRD) strategies to define patients destined to relapse after surgery for treatment escalation whilst disease burden is low and B) assess the impact of neoantigen reactive T cells targeting multiple clonal antigens to attempt to delay drug resistance and improve survival.

Top 5 publications

Watkins, T.B.K et al. Pervasive chromosomal instability and karyotype order in tumor evolution Nature. 2020 Nov;587(7832):126-132
Rosenthal R, et al; TRACERx consortium. Neoantigen directed immune escape in lung cancer evolution Nature, 2019. Mar;567(7749):479-485
McGranahan, N et al. Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution Cell (2017) Nov 30;171(6):1259-1271
Jamal-Hanjani, M et al. TRACERx . Tracking Non-Small Cell Lung cancer Evolution New England Journal of Medicine (2017) 26^th April 2017
AbboshC et al. Phylogenetic circulating tumor DNA analysis depicts early stage lung cancer evolution. Nature Article 26^th April 2017

Bart Vanhaesebroeck has discovered multiple roles for PI3-kinase inhibition in cancer and immunotherapy currently in clinical trials.

Research

My group plays a leading role in the study of PI 3-kinases (PI3Ks). These cell signalling enzymes are deregulated in cancer, overgrowth syndromes, inflammation and auto-immunity and several other human diseases. By investigating the mechanisms and physiological processes regulated by PI3Ks, our studies have underpinned the development, clinical strategies and approval of specific PI3K inhibitors for leukaemia and their emerging use in solid tumour immunotherapy.

With support from the BRC (High Impact Initiative 2014), we have now developed the first small molecule activators of PI3K (Nature, submitted for publication). This has opened a new field of research and also turns more than two decades of PI3K drug development on its head. We anticipate that PI3K activators are the next frontier in PI3K drug development, with an even broader range of therapeutic indications than PI3K inhibitors, including in cancer, immune stimulation, tissue regeneration (such as neuroregeneration) and tissue protection (eg. reperfusion following stroke or heart attack).

High impact

I discovered the PI3Kδ family member and have taken this discovery ‘from the bench to the clinic’. PI3Kδ inhibitors are now approved for use in B-cell malignancies, and are the most active area of PI3K drug development, with ongoing exploration for use in leukaemia, solid tumours and immune/inflammatory conditions.
Our finding that PI3Kδ inhibition can stimulate cancer immunity (Nature 2014:509:407) is now being tested in several cancer immunotherapy trials world-wide, one of which I instigated in the UK, in collaboration with Cancer Research UK, Amgen US and the Southampton CRUK Centre (ClinicalTrials.gov Identifier: NCT02540928). This trial has now been concluded and written up (Nature, under review), with data that have the potential to catapult PI3Kδ inhibition to the forefront of immunotherapy in solid tumours.

Future Plans

to understand the fundamental principles of PI3K signalling
to make PI3K inhibitors work in the clinic
to further develop the exciting new field of PI3K activators, both at the level of fundamental research and translation, including the creation of a spin-out. Discussions with funders (including MRC, CRUK, ARUK and VCs) are in progress. Our long-term aim is to develop PI3K activators for human therapy, including in cancer.

Top 5 publications

Vanhaesebroeck B, et al. inhibitors are finally coming of age. Nat Rev Drug Discov. 2021.
Lechner M, et al. Somatostatin receptor 2 expression in nasopharyngeal cancer is induced by Epstein Barr virus infection: impact on prognosis, imaging and therapy. Nature communications. 2021;12(1):117.
Berenjeno IM, et al. Oncogenic PIK3CA induces centrosome amplification and tolerance to genome doubling. Nature communications. 2017;8(1):1773.
Castillo SD, et al. Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans. Science translational medicine. 2016;8(332):332ra43.
Ali K, et al. Inactivation of PI(3)K p110delta breaks regulatory T-cell-mediated immune tolerance to cancer. Nature. 2014;510(7505):407-11.

Kwee Yong is myeloma specialist and chief investigator for national trials with programme of research into immune microenvironment.

Research

My laboratory research focusses on 3 main themes in multiple myeloma (1) immune dysfunction, (2) developing bench to bedside therapies and (3) precursor conditions, monoclonal gammopathy and smouldering myeloma. In immune dysfunction we study the way in which T cell differentiation and markers of exhaustion correlate with clinical outcomes of chemotherapy and stem cell transplantation, utilising ex-vivo systems and samples from my Phase 3 NCRN trial in newly diagnosed patients (Myeloma XV. We have developed first-in-human combinations of PI3k inhibitors (BUBBLE study, NCRN….), first ligand based CAR-T study in myeloma, Auto-2, and our current CAR-T study, Mcarty is going through regulatory review.

In precursor disease, partnering with investigators at Harvard, Oxford and the ICR, we are studying how genomic features combine with immunological function in the host bone marrow to alter risk of progression to frank malignancy. I have set up the NCRN observational study in smouldering myeloma, COSMOS (https://cosmos-myeloma.org.uk/), recruiting patients throughout the UK for this work, and streamlining patient management. The aim is to develop new refined models of progression, and identify interventional strategies for those at highest risk of progression.

High impact examples

My NCRN study in newly diagnosed myeloma, CARDAMON, challenged the current practice of stem cell transplantation in first remission. Cardamon, and its predecessor study, PADIMAC, provide evidence that patients whose bone marrow is clear of minimal residual disease after induction chemotherapy can be safely assigned to a no-transplant pathway, with potential healthcare savings and improved wellbeing (Yong et al, J Clin Onc 2021; 15, Suppl). RNA sequencing in PADIMAC revealed a gene signature that predicts good response to bortezomib, with potential to avoid transplantation (Chapman, Blood 2018).
My work on the APRIL-BCMA ligand-receptor system (Quinn et al, Blood 2014, Lee, Br J Haem 2016) contributed to scientific rationale for the development of BCMA targeted immunotherapies that are currently the leading new agents for this cancer.
My doctoral student developed the first ligand based chimeric antigen receptor (CAR) T cell therapy for myeloma, that resulted in a Phase I clinical trial (Lee, Blood 2018).
My collaborative work on smouldering myeloma has contributed to the evidence base for improved genomic characterisation of these patients (Bustoros, J Clin Onc 2020)
My work investigating host immune function in the bone marrow has shown for the first time that markers of T cell suppression and exhaustion associate with increased risk of relapse following chemotherapy and stem cell transplantation, providing rationale for immune-based interventions (Alrasheed, Clin Can Res 2020, Lee, Front Immunol, 2021)

Future plans

Develop and publish evidence for role of immune function and anti-tumour T cell reactivity in the progression of smouldering myeloma, thus providing the basis for designing immune based therapies
In early detection and pre-malignancy, design and implement an interventional study for those patients with smouldering myeloma at highest risk of progression. Patient selection and intervention will be based on data from current CRUK programme work investigating genomic and immunological contributors to risk
Complete the Phase 3 NCRN study, Myeloma XV, and publish preliminary results on this stratified approach to intensifying therapy for high risk patients, while de-escalating treatment for low risk patients
Complete first-in-human dual antigen targeting CAR-T study in myeloma, providing evidence for this modular approach to augmenting efficacy of re-directed therapy, publishing results and developing follow on study for relapsed patients who have exhausted approved therapies

Top 5 publications from 2015

Lee L, Alrasheed N, Khandelwal G, Fitzsimons E, Richards H, Wilson W, Chavda SJ, Henry J, Conde L, De Massy MR, Chin M, Galas-Filipowicz D, Herrero J, Chain B, Quezada SA, Yong K. Increased Immune-Regulatory Receptor Expression on Effector T Cells as Early Indicators of Relapse Following Autologous Stem Cell Transplantation for Multiple Myeloma. Frontiers in Immunology 2021; 12: 618610
Alrasheed N, Lee L, Ghorani E, Henry JY, Conde L, Chin M, Daria Galas-Filipowicz, … Quezada SA*, Yong KL* Marrow Infiltrating Regulatory T Cells Correlate with the Presence of Dysfunctional CD4+PD-1+ Cells and Inferior Survival in Patients with Newly Diagnosed Multiple Myeloma. Clinical Cancer Research. 2020; 26:3443-3454.
Chapman MA, Sive J, Ambrose J, Roddie C, Counsell N, Lach A, Abbasian M, Popat R, Cavenagh JD, Streetly MJ, Schey S, Koh M, Virchis AE, Crowe J, Quinn MF, D’Sa S, Cook G, Crawley CR, Pratt G, Cook M, Braganza N, Adedayo T, Smith P, Clifton-Hadley L, Owen R, Keats JF, Herrero J, Yong K.^.RNA sequencing of newly diagnosed patients in the PADIMAC study leads to a bortezomib/lenalidomide decision signature. Blood 2018 132(20):2154-2165
Lee L, Draper B, Chaplin N, Philip B, Chin M, Galas-Filipowicz D, Onuoha S, Thomas S, Baldan V, Bughda R, Maciocia P, Kokalaki E, Neves M, Patel D, Rodriguez-Justo M, Francis J, Yong K*, Pule M*. An APRIL Based Chimeric Antigen Receptor for Dual Targeting of BCMA and TACI in Multiple Myeloma. Blood, 2018; 31:746-758 *equal contribution
Koutoukidis DA, Land J, Hackshaw A, Heinrich M, McCourt O, Beeken RJ, DeSilva D, Rismani A, Popat R, Kyriakou C, Papanikolaou X, Mehta A, Paton B, Fisher A, Yong KL. Fatigue, Quality of Life and Physical Fitness Following an Exercise Intervention in Multiple Myeloma Survivors (MASCOT): An Exploratory Randomised Phase 2 Trial Utilising a Modified Zelen Design’. British Journal of Cancer. 2020; 123: 187–95.

Other information

Cancer Research UK Early Detection programme grant awarded 2019. I led the effort of senior investigators at Dana Farber Cancer Institute, Harvard University, Oxford University and the Institute of Cancer Research, to secure this programme that will enable us to coordinate transatlantic efforts to understand and intercept the development of cancer in this rare patient group.
Survivorship programme in myeloma. My work on physical activity and exercise has provided the evidence for the safety and benefit of exercise in myeloma (Groeneveldt, BMC Cancer, 2013). In collaboration with Institute of Epidemiology and Healthcare, I led the MASCOT study, confirming that exercise reduces fatigue and improve quality of life in myeloma survivors (British Journal of Cancer 2020) and providing the basis for a doctoral project on prehabiliation exercise in transplant patients.
Real world evidence in myeloma. In 2015 I led a real world study across 7 European countries, mapping the treatment pathways and experience of myeloma patients receiving chemotherapy. The results, published in Brit J Haematology in 2016, provided for the first time, evidence for the marked attrition of patients between first and third line therapy, and the great increase in treatment and disease burden at relapse. This work is amongst my most highly cited, and provides the benchmark to assess new therapies.
Frequent invited talks at national and international meetings.

Key positions held

Senior leadership team, Myeloma Research Alliance, subgroup of Haematology-Oncology NCRI Clinical studies group
Member, NCRI Haemato-Oncology Clinical Studies group
Member, CRUK Research Careers committee
Elected Fellow, College of Myeloma, UK Myeloma Forum