Research

CRUK National Biomarker Centre- Caroline Dive

After completing her PhD studies in Cambridge, Caroline moved to Aston University's School of Pharmaceutical Sciences in Birmingham where she started her own group studying mechanisms of drug induced tumour cell death. She then moved to what became the Faculty of Life Sciences at The University of Manchester to continue this research. Caroline was awarded a Lister Institute of Preventative Medicine Research Fellowship before moving to the CRUK Manchester Institute in 2003. Here she set up the Clinical and Experimental Pharmacology Group interfacing with the Derek Crowther Unit for early clinical trials at The Christie. To reflect the focus on biomarker research, the group changed its name to the Cancer Research UK Manchester Institute Cancer Biomarker Centre in 2019. Caroline is currently a Senior Group Leader at the CRUK Manchester Institute and Professor of Pharmacology at The University of Manchester.

Throughout her career, Caroline has attracted several prizes and awards, most notably she was awarded the Pasteur-Weizmann/Servier International Prize in 2012, the AstraZeneca Prize for Women in Pharmacology in 2016 and in 2019, the Heine H. Hansen Lectureship Award by the International Association for the Study of Lung Cancer (IASLC). She is a fully elected member of EMBO (2020), an elected Fellow of the Academy of Medical Sciences (2015), Fellow of the British Pharmacological Society (2012) and Fellow of the European Academy of Cancer Sciences (2011). In 2017, Caroline was awarded Commander of the Order of the British Empire (CBE) for her services to cancer research. Most recently, Caroline was presented with the first Johann Anton Merck Award in 2020 for outstanding preclinical research in oncology, and is the EACR President 2020 – 2022.

EACR Conference

Introduction | Liquid Biopsies | The European Association for Cancer Research (eacr.org) [eacr.org]

Introduction
Research Projects
Selected Publications
Team

Introduction

Cancer Precision Medicine at its foundation requires biomarker-informed patient management to maximise benefit and reduce harm. Biomarkers that emanate from discoveries in both basic science and reverse translation from the clinical observations are needed for all aspects of a cancer patient’s ‘journey’, from the pre-disposition and early detection of cancer through to best care in advanced disease. Successful development of clinical decision-making biomarkers requires:

a range of dedicated facilities and specialised skill sets
integration of different disciplines
access to large and appropriate patient cohorts
extensive early phase clinical trial activities
access to innovative technology platforms, with high sensitivity and specificity
dedicated and sustainable biobanking
organised analytical, management and reporting processes compliant with regulatory authorities
partnerships for biomarker commercialisation enabling entry to the NHS and routine clinical use

We have built all of these elements into the CBC with > 100 staff within laboratories for tumour biology, biomarker discovery and preclinical pharmacology research alongside regulated laboratories for biomarker assay validation and qualification within clinical trials to Good Clinical Practice standards supporting clinical decision-making. Critically, we have established strong links to The Christie NHS Foundation Trust, the largest comprehensive, dedicated and research active cancer hospital in Western Europe receiving over 15,000 new cancer patients each year and the hub of an extensive developed cancer delivery network across 3.2 million people.

Centre is composed the following integrated teams:

The Preclinical Pharmacology (PP) Team conducts the preclinical studies of CBC research, with their own focus on the biology of small cell lung cancer (SCLC). This team developed novel circulating tumour cell patient derived explant models (CDX) and uses them to explore SCLC genomes and phenotypes and to test novel therapies (see Hodgkinson et al Nature Medicine 2014; Simpson et al, Nature Cancer 2020; Schenk et al Nature Comms. 2022; Lallo et al Clinical Cancer Research 2018).

The Tissue Biomarkers (TB) Team studies tumour cells and tumour microenvironments within patient-derived preclinical model tumours and clinical biopsies.

Translational Immunology (TI) Team supports biomarker sciences for immune-based therapeutics, including analysis of immune cell populations and cytokines in liquid biopsies and in tumours working in tandem with the Tissue Biomarkers team. A recent highlight has been the identification of plasma Tie2 to optimise anti-angiogenic treatment in colorectal cancer (Jayson et al, Nature Communications 2018). Additionally, the team are developing ex vivo culture platforms to assess and predict patient response to current and novel immunotherapies in various cancers.

The Nucleic Acids Biomarkers (NAB) Team develop, validate and analyse liquid biopsies based on circulating tumour (ct)DNA, circulating RNA and circulating tumour cells (CTCs) (see Carter et al Nature Medicine 2017). This team is using ctDNA methylation profiling for the detection and molecular subtyping of cancer (Chemi et al Nature Cancer 2022) and ctDNA mutation profiling, for example to assist trial selection for patients entering the Christie NHS Foundation Trust Phase I Trials Unit (see Rothwell et al Nature Medicine 2019). Enumeration and profiling of ‘early’ CTCs is employed to explore risk of disease recurrence after surgery and identification of metastatic subclones in non-small cell lung cancer (Chemi et al Nature Medicine 2019).

The Bioinformatics and Biostatistics (BBS) Team works closely with all teams to analyse preclinical and clinical data sets, develop and deploy robust computational pipelines and provide upfront statistical support to study designs (see Chemi et al Nature Cancer 2022).

The digital Experimental Cancer Medicines Team (dECMT) is the most ‘clinic facing’ team in the CBC, integrating biomarker and clinical data and providing digital solutions for visualisation. This team facilitates patient involvement in their own trials and testing of digital devices in the home.

Our Quality Assurance (QA) Team advise on assay method validation, perform internal audits of our regulated research and ensure that we are compliant with Good Clinical Practice and EU/UK regulations for clinical trial specimen analyses.

The Operations Team ensures all biomarker projects are managed effectively with respect to regulatory paperwork, project costings, sample handling and project deadline delivery.

The Administration Team provides administrative support to the Director and the Centre staff, coordinate non-scientific operations, support grant submissions and provide administrative support for the Manchester ECMC and the CRUK Lung Cancer Centre.

The CRUK MI CBC supports the Manchester Experimental Cancer Medicine Centre, the CRUK Lung Cancer Centre of Excellence, the precision medicine theme of Manchester’s NIHR Biomedical Research Centre, the recently established CRUK RADNET network and the ACED Alliance for the early detection of cancers. We are members of both the CRUK Precision-Panc consortium, profiling ctDNA in national cohorts of pancreas cancer patients, and the ACRCelerator Award developing preclinical models to translate findings to clinical improvements in colorectal cancers. Most recently, we established the UPSMART CRUK Accelerator to operationalise digital clinical trials across the CRUK ECMC network and with partners in Italy and Spain. The CBC is currently training six PhD students, and four clinical fellows.

Small cell lung cancer

Small cell lung cancer (SCLC) is an aggressive, highly metastatic, and incurable neuroendocrine cancer. This disease forms an important focus for the Cancer Biomarker Centre, and to contribute clinically relevant lung cancer research, CBC established a longstanding partnership with Prof Fiona Blackhall, a Professor in Thoracic Oncology at The University of Manchester and Lung Disease Group Chair at the Christie NHS Foundation Trust.

Patient derived preclinical models reveal novel biology of SCLC

The Preclinical Pharmacology (PP) team continues to expand the diversity of our biobank of CDX (currently >60 models). Several CDX were derived from patients before treatment with immune checkpoint inhibitors and following disease progression, facilitating discovery of tumour intrinsic predictive biomarkers for response to this recently licensed therapeutic option. In 2020, the team reported a new SCLC subtype driven by ATOH1, a neuroendocrine transcription factor not previously known to play a role in SCLC. They discovered that ATOH1 mediates a distinct transcriptional program, and both genetic and pharmacological targeting of this program increased cell death, implicating ATOH as a potential therapeutic target. They also exploited our pre and post chemotherapy CDX to discover a novel mechanism of acquired chemoresistance (an almost universal clinical occurrence), involving soluble guanylate cyclase that drives a nitric oxide-dependent signalling cascade culminating in activation of protein kinase G (see Schenk et al. Nat Commun. 2021;12(1):6652.) another potentially tractable target.

SCLC vasculogenic mimicry, perfusable tumour derived vessels

The PP team has continued to study ‘plasticity’ of SCLC cells, in this case exemplified by their ability to mimic endothelial cell behaviours via vasculogenic mimicry (VM). Having shown that VM vessels frequently contained red blood cells, they utilised a fluorescent lectin that interacts with glycoproteins in the basement membrane in vivo which labelled inner walls of both endothelial (CD31 positive) and VM (CD31 negative) vessels inferring perfusion with functional connectivity between VM vessels and the endothelium (Figure 1).

**Figure 1:** **Intravenous tomato lectin injection to reveal perfusion of endothelial (EC) and vasculogenic mimicry vessels in CDX tumours**. Lectin labels glycoproteins lining the inside of functional vessels and immunofluorescent staining of resected tumours lit up both CD31+/(green)/lectin+ (red) EC vessels (yellow arrow, merge) and CD31-/lectin+ VM vessels (white arrow, merge). Human anti-mitochondria staining shows presence of CDX tumour cells. Representative image from CDX19, also observed in other CDX (data not shown). Scale bars, 50 µm.

The first CDX model of an extra-pulmonary neuroendocrine carcinoma

Extra-pulmonary neuroendocrine carcinomas (EP-NECs) have limited treatment options and are poorly understood biology. In collaboration with Prof Juan Valle and Dr Mairead McNamara from the Christie NHS Foundation Trust, the PP team has generated and characterised the first CDX model of EP-NEC, and after histopathology (Figure 2) and RNAseq analysis, identified it as a Merkel Cell Carcinoma (MCC) EP-NEC, which prompted a review of the donor patient’s original diagnosis. This CDX recapitulated the biology and chemotherapy response of the donor patient’s tumour and holds potential as an avatar to guide future treatment.

**Figure 2:** Histopathology analysis of donor biopsy and derived CDX tumour at showing similar neuroendocrine carcinoma morphology and expression of diagnostic markers (PanCKs, pan-cytokeratins, SYP, Synaptophysin, NCAM, Neural cell adhesion molecule, CGA, Chromogranin A). Scale bar (black line), 50 μm.

SCLC Immunology

The Cells and Proteins (CAP) team has developed methods for ex vivo co-culture of immune cells (peripheral blood lymphocytes or Natural Killer (NK) cells) and disaggregated SCLC CDX cells to enable investigation of anti-tumour immune responses and resistance to immunotherapy (Figure 3). Early data suggest differential susCBCtibility between CDX models, as well as between the neuroendocrine and non-neuroendocrine CDX subpopulations within models, to NK cell-mediated killing. To complement these ex-vivo studies, an IHC assay against the NK cell reCBCtor NKp46 is being optimised for detection of tumour infiltrating NK cells. Generation of new CDX models (four so far), with banking of matched PBMCs from donors receiving immunotherapy, is also underway to progress co-culture research and study adaptive immune biology.

**Figure 3:**Tumour cells are disaggregated for ex-vivo culture from CTC Derived Explant Models (CDX) grown in mice. Neuroendocrine (NE) tumour cells float in culture in contrast to Non-NE cells, which are adherent allowing physical separation of these differing phenotypes. NE and Non-NE tumour cells are co-cultured with Natural killer (NK) cells isolated from a healthy volunteer or patient’s blood to determine the extent of NK-cell mediated tumour cell killing. This system is being developed to understand the mechanisms used by tumour cells to escape NK-cell killing and to test the effect of therapeutics.

Subtyping SCLC via DNA methylation profiling of ctDNA

The recent description of molecular subtypes of SCLC with preclinical evidence of subtype vulnerabilities affords a ‘horizon view’ of personalised medicines for patients with this recalcitrant cancer. Given the paucity of adequate tumour biopsies, a blood test to subtype each patient will support this goal. The Nucleic Acids Biomarkers and Bioinformatics & Biostatistics teams have combined their expertise to optimise our genome-wide circulating free (cf)DNA methylation assay (T7-MBD-seq), with a bespoke bioinformatics pipeline and R package for analysis. They applied this pipeline to profile DNA methylation in >1,300 samples, including 593 cfDNA samples, across several studies including SCLC CDX and cfDNA from patients with SCLC (in collaboration with Prof Charles Rudin at Memorial Sloane Kettering Cancer Center, New York). Together they have developed a sensitive tumour/normal prediction classifier for disease monitoring and utilised differences in methylation patterns between the predominant molecular subtypes, based on NE transcription factors ASCL1, NEUROD1 and a double negative, to derive a molecular subtype classifier. These blood tests are now being validated in clinical cohorts.

Cancer of Unknown Primary – taking the U out of CUP

The Nucleic Acids Biomarkers and Bioinformatics & Biostatistics teams have also studied DNA methylation to develop a tissue-of-origin classifier to support treatment decisions in cancer of unknown primary (CUP) study in collaboration with Dr Natalie Cook, Christie NHS Foundation Trust. CUP describes a metastatic cancer cohort, with unknown primary tumour, making selection of beneficial treatment challenging. Tissue-of-origin classifiers were trained on methylation array data from 8892 samples, across 33 cancer types. These classifiers are in the late stages of development (Figure 4).

**Figure 4: Tissue of origin classifiers in cfDNA to support management of Cancers of Unknown Primary**. A) Pan cancer methylation array data undergo conversion and in silico spike in to non-cancer control cfDNA reads acting as a ‘cfDNA mimic’. B) An ensemble of Xgboost classifiers is trained on and then tested for each tumour type. C) Each tumour classifier is validated on cfDNA samples from patients with known tumour types and applied to cohort of cfDNA samples from patients with Cancer of Unknown Primary for tumour type prediction.

Bioinformatics for cfDNA methylation assays

The BBS team used a Nextflow framework to create a robust and reproducible data processing workflow enabling capture of quality control metrics and metadata. Using a novel approach, BBS converted data from methylation arrays (an unsuitable approach for cfDNA) including published data on SCLC and data from a range of tumour generated within The Cancer Genome Atlas consortium (TCGA) to comply with NAB cfDNA sequencing data. Machine learning was applied to detect presence or absence of tumour-derived DNA in plasma (ctDNA), SCLC molecular subtypes and tissue-of-origin for CUP.

ctDNA liquid biopsy biomarkers to direct therapy decisions: CACTUS, DETECTION and DYNAMIC trials in Melanoma

Guided by basic and translational research from Prof Richard Marais’ group at CRUK Manchester Institute, the Nucleic Acids Biomarkers (NAB) team, supported by our Quality Assurance team, have developed our portfolio of GCP-compliant liquid biopsy trials including CACTUS, DETECTION and DYNAMIC trial in partnership with Prof Paul Lorigan and Dr Rebecca Lee (UoM/CFT). The CACTUS trial (CirculAting Tumour DNA gUided therapy Switch) uses a ddPCR ctDNA assay to measure mutated BRAF levels that instruct treatment switch from targeted to immunotherapy for advanced cutaneous melanoma: 37 patients have been screened and validated ctDNA data returned to clinic within 7 days. The DETECTION trial (Circulating tumour DNA guidEd Therapy for stage IIB/C BRAF or NRAS mutant- positive mElanoma after surgiCal resecTION) opened to recruitment in late 2021. DETECTION involves ddPCR ctDNA analysis to detect early relapse/micro-metastatic disease and select patients for targeted therapy using a panel covering 3 BRAF, 4 NRAS and 2 hTERT mutations. NAB delivers the first validated DETECTION assay in January 2022; sequential samples from up to 900 patients are expected over the next decade. NAB are also validating cfDNA ddPCR assays to monitor tumour activity and burden (TAB) levels for the upcoming DYNAMIC trial (Circulating tumour DNA guided Adaptive BRAF and MEK Inhibitor therapy), which uses BRAF V600 ddPCR assays to monitor TAB to inform adaptive BRAF-MEK inhibitor therapy in Stage III unresectable/IV cutaneous melanoma.

cfDNA profiling to support drug development

The Nucleic Acids Biomarkers team are also working with UCB and CARRICK therapeutics to identify cfDNA biomarkers for patient response in their phase I/II clinical trials of UCB6114 (a mAb optimised targeting the human gremlin-1 protein) and the CDK7 inhibitor samuraciclib, respectively.

Biomarkers to inform immunotherapy trials

Reflecting unmet clinical need, the Cells and Proteins team continue to expand the CBC immune biomarker ‘toolkit’. Through a partnership with ThermoFisher, T-cell reCBCtor sequencing assays have been optimised to reveal T-cell reCBCtor clonality, diversity and convergence in blood samples. An early study using these assays involves a pilot set of longitudinal samples from NSCLC patients receiving immunotherapy/chemotherapy combination with ongoing clonal analysis of patient profiles by the BBS team.

CRUK Manchester Institute basic science biomarker discovery to the clinic

Working with Dr Santiago Zelenay at the CRUK Manchester Institute, the Cells and Proteins team has developed an assay to assess his COX_IS gene signature in FFPE patient samples using the clinically compatible Nanostring platform to validate its prognostic and/or predictive clinical value. Emerging data shows good intra and inter-assay reproducibility for analysis of clinical samples. Our ACED funded PhD student, also working jointly with Zelenay’s group, has analysed COX-IS and other immune/inflammatory gene signatures in early stage lung cancer resections to assess if there are associations with risk of disease relapse. A complementary COX2 IHC assay shows correlation between COX2 gene (Figure 5) and protein expression and is included in a multiplex IHC panel of 24 markers being established in collaboration with Prof Lisa Coussens (Oregon Health Science University) to enable assessment of expression levels and spatial distribution of immune cells within the tumour microenvironment and ultimately relationships with patient outcomes.

**Figure 5:** COX-2 protein expression in non-small lung cancer measured by immunohistochemistry. A, B: Representative images of squamous cell carcinoma expressing high and low levels of COX-2 in tumour and normal tissue, respectively. C, D: Adenocarcinoma expressing high and low levels of COX-2 in tumour. T = tumour, S = stroma, N = normal lung tissue (pneumocytes).

Community based blood sampling

The Cells and Proteins team and digital Experimental Cancer Medicine Team (ECMT), in partnership with Fiona Thistlethwaite from the Christie, assessed the feasibility of detecting 15 cytokines by ELISA in as little as 30µl blood collected using a micro-sampler device and optimised workflows for sample processing and analysis. This approach is being applied in the NOTION trial to evaluate home-based blood sampling kits that allow assessment of cytokines as an ‘early warning’ system of adverse events and cytokine release syndrome in patients receiving immunotherapy and advanced T-cell therapies.

Bioinformatics and Biostatistics across the Cancer Biomarker Centre

The Bioinformatics and Biostatistics (BBS) team integrates bioinformatics and statistical methods for its many and varied projects including specialised methods for single cell analysis to classify CTCs. They advise on the statistical powering of experimental designs including for the NOTION trial (described above) and the VALTIVE1 trial, the objective of which is to qualify plasma Tie2 for clinical decision making around anti-angiogenic agents in ovarian cancer in partnership with Prof Gordon Jayson (The Christie/University of Manchester), and the Accelerometer trial as part of our CRUK UpSMART Accelerator Award, coordinated by digital ECMT. The TARGET trial, led by Cancer Biomarker Centre alumnus, Dr Matt Krebs (The Christie/University of Manchester), matching patients with a broad range of advanced cancers to early phase clinical trials is now complete. Within TARGET, the Nucleic Acids Biomarkers and BBS teams have analysed and reported somatic mutations and copy number alterations across a 641 cancer-associated gene panel in a single ctDNA assay. The latest BBS data processing workflow was used to rerun all the ctDNA analyses producing a rich, internally consistent retrospective dataset now available to researchers to test hypotheses.

Digital solutions to support treatment for cancer patients

The digital Experimental Cancer Medicine Team seeks to digitally empower patients and healthcare professionals to innovate and design new cancer care pathways. They provide next generation patient cancer care through comprehensive data-driven evidence, enabling transformation of clinical decision-making, evolving the role of the patient and improving patient outcomes. This is achieved by listening to patients and healthcare professionals, understanding their needs and working proactively with them to develop ethical algorithms (AI) to support patient care, building digital solutions and evaluating technologies under clinical trial conditions (technology clinical trials).

Examples of digital ECMT’s distinctive research include: (i) The IN-HOME study, assessing feasibility of Acute Kidney Injury (AKI) detection in the patient’s home; Part A demonstrated feasibility and Part B is now opened to recruitment, evaluates potential for earlier diagnosis of AKI/change in renal function in cancer patients with intensive home monitoring. (ii) The A-EYE study, developing new AI methods to detect adverse retinal abnormalities associated with cancer treatment, now open to recruitment at the Manchester Royal Eye Hospital with >240 patients recruited. (iii) The NOTION study (with the Cells and Proteins team), enabling dry blood spot technology to measure cytokine levels in the home for early detection of immune related toxicities. (iv) The eTARGET tool, a digital solution integrating clinical and genomic data, histopathology data and corresponding images in a single portal to support decision making by Molecular Tumour Boards and deployed in two clinical trials being led from the Christie (TARGET National and CUP-COMP). eTARGET incorporated a link to the digital ECMT Cancer Trial Matching tool supporting clinical decision making by matching a cancer patient’s tumour genetic profile to optimal clinical trials. (vi) dECMT Artificial Intelligence (AI) researchers, business analysts and software engineers continued to improve the CORONET tool (COVID-19 risk in Oncology Evaluation Tool) using new datasets alongside input from the BBS team and our clinical colleagues. The CORONET team were recognised as “trailblazers in COVID-19 Research Response” at the NIHR Clinical Research Network Greater Manchester’s Evening of Excellence in November 2021. (vii) With colleagues in Italy and Spain, digital ECMT continued to lead our CRUK Accelerator Award, UpSMART to enable SMART Experimental Cancer Medicine Trials. Six Digital Healthcare Products (DHPs) were made available to the network of 24 sites (Figure 6) and with six more DHPs prioritised for the coming year. (viii) digital ECMT joined a consortium led by Vall d’Hebron (Barcelona) to secure EU Horizon 2020 funding for CCE_DART (Building Data Rich clinical Trials) with partner sites across Europe.

**Figure 6:** Summary of UpSMART Digital Healthcare Products (DHPs) currently available to the consortium at the end of 2021. 1) Digital ECMT Cancer Trial Matching Tool. 2) Cancer Trial Finder Template. 3) eTARGET - presents a single view of patient clinical and genomic NGS data to support decision making for a Molecular Tumour Board (MTB). 4) CORONET - online tool to support decisions regarding hospital admissions or discharge in cancer patients presenting with COVID-19. 5) PIPO - Phase 1 Prognostic Online - online tool used as an objective way for predicting the overall survival outcomes in patients prior to enrolment on early phase clinical trials. 6) ACUITY - an open source visual analytics system, which allows early clinical study data exploration and hypothesis generation at both the individual subject and study population level to support timely and effective decision-making.

Selected Publications

Schenk MW, Humphrey S, Hossain ASMM, Revill M, Pearsall S, Lallo A, Brown S, Bratt S, Galvin M, Descamps T, Zhou C, Pearce SP, Priest L, Greenhalgh M, Chaturvedi A, Kerr A, Blackhall F, Dive C, Frese KK. (2021)
Soluble guanylate cyclase signalling mediates etoposide resistance in progressing small cell lung cancer.
Nature Communications 12(1):6652. PubMed abstract (PMID: 34789728)

Payapilly A, Guilbert R, Descamps T, White G, Magee P, Zhou C, Kerr A, Simpson KL, Blackhall F, Dive C, Malliri A. (2021)
TIAM1-RAC1 promote small-cell lung cancer cell survival through antagonizing Nur77-induced BCL2 conformational change.
Cell Reports 37(6):109979. PubMed abstract (PMID: 34758330)

Mahmood RD, Shaw D, Descamps T, Zhou C, Morgan RD, Mullamitha S, Saunders M, Mescallado N, Backen A, Morris K, Little RA, Cheung S, Watson Y, O'Connor JPB, Jackson A, Parker GJM, Dive C, Jayson GC. (2021)
Effect of oxaliplatin plus 5-fluorouracil or capecitabine on circulating and imaging biomarkers in patients with metastatic colorectal cancer: a prospective biomarker study.
BMC Cancer 21(1):354. PubMed abstract (PMID: 33794823)

Hall C, von Grabowiecki Y, Pearce SP, Dive C, Bagley S, Muller PAJ. (2021)
iRFP (near-infrared fluorescent protein) imaging of subcutaneous and deep tissue tumours in mice highlights differences between imaging platforms.
Cancer Cell International 21(1):247. PubMed abstract (PMID: 33941186)

Foy V, Lindsay CR, Carmel A, Fernandez-Gutierrez F, Krebs MG, Priest L, Carter M, Groen HJM, Hiltermann TJN, de Luca A, Farace F, Besse B, Terstappen L, Rossi E, Morabito A, Perrone F, Renehan A, Faivre-Finn C, Normanno N, Dive C, Blackhall F, Michiels S. (2021)
EPAC-lung: European pooled analysis of the prognostic value of circulating tumour cells in small cell lung cancer.
Translational Lung Cancer Research 10(4):1653-1665. PubMed abstract (PMID: 34012782)

Chemi F, Rothwell DG, McGranahan N, Gulati S, Abbosh C, Pearce SP, Zhou C, Wilson GA, Jamal-Hanjani M, Birkbak N, Pierce J, Kim CS, Ferdous S, Burt DJ, Slane-Tan D, Gomes F, Moore D, Shah R, Al Bakir M, Hiley C, Veeriah S, Summers Y, Crosbie P, Ward S, Mesquita B, Dynowski M, Biswas D, Tugwood J, Blackhall F, Miller C, Hackshaw A, Brady G, Swanton C, Dive C; TRACERx Consortium. (2019)
Pulmonary venous circulating tumor cell dissemination before tumor resection and disease relapse.
Nature Medicine 25(10):1534-1539. PubMed abstract

Rothwell DG, Ayub M, Cook N, Thistlethwaite F, Carter L, Dean E, Smith N, Villa S, Dransfield J, Clipson A, White D, Nessa K, Ferdous S, Howell M, Gupta A, Kilerci B, Mohan S, Frese K, Gulati S, Miller C, Jordan A, Eaton H, Hickson N, O'Brien C, Graham D, Kelly C, Aruketty S, Metcalf R, Chiramel J, Tinsley N, Vickers AJ, Kurup R, Frost H, Stevenson J, Southam S, Landers D, Wallace A, Marais R, Hughes AM, Brady G, Dive C, Krebs MG. (2019)
Utility of ctDNA to support patient selection for early phase clinical trials: the TARGET study.
Nature Medicine 25(5):738-743. PubMed abstract

Carter L, Rothwell D, Mesquita B, Smowton C, Leong HS, Fernandez-Gutierrez F, Li Y, Burt D, Antonello J, Morrow C, Hodgkinson C, Morris K, Priest L, Carter M, Miller C, Hughes A, Blackhall F, Dive C, Brady G. (2017)
Molecular analysis of circulating tumor cells identifies distinct copy-number profiles in patients with chemosensitive and chemorefractory small-cell lung cancer.
Nature Medicine 23(1):114-119. PubMed abstract

Williamson S, Metcalf R, Trapani F, Mohan S, Antonello J, Abbott B, Leong HS, Chester C , Simms N, Polanski R, Nonaka D, Priest L, Fusi A, Carlsson F, Carlsson A, Hendrix M, Seftor R, Mrs. Elisabeth Seftor, Rothwell D, Hughes A, Hicks J, Miller C, Kuhn P, Brady G, Simpson K, Blackhall F, Dive C. (2016)
Vasculogenic Mimicry in Small Cell Lung Cancer.
Nature Communications 7:13322. PubMed abstract

Hodgkinson CL, Morrow CJ, Li Y, Metcalf RL, Rothwell DG, Trapani F, Polanski R, Burt DJ, Simpson KL, Morris K, Pepper S, Nonaka D, Greystoke A, Kelly P, Bola B, Krebs MG, Antonello J, Ayub M, Faulkner S, Priest L, Carter L, Tate C, Miller CJ, Blackhall F, Brady G & Dive C. (2014)
Tumorigenicity and genetic profiling of circulating tumor cells in small-cell lung cancer.
Nature Medicine 20(8):897-903. PubMed abstract

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