WORLD CLASS BASIC, TRANSLATIONAL AND CLINICAL RESEARCH

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 most basic of the CBC research with their own focus on the biology of 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, Lallo et la Clinical Cancer Research 2018).  

The Tissue Biomarkers (TB) Team studies tumour cells and tumour microenvironments within patient-derived preclinical model tumours and clinical biopsies. In 2020, the TB team is merging with the Christie Hospital Academic Pathology Unit, working in tandem with specialised cancer pathologists and supporting pathology training.

The Cells and Proteins (CAP) Team develops and validates liquid biopsy assays for clinical trial utility focusing on circulating tumour cells and proteins. CAP recently established the Tumour Immunology and Inflammation Monitoring Laboratory (TIIML) to support 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).

The Nucleic Acids Biomarkers (NAB) Team develop, validate and analyse liquid biopsies based on circulating tumour (ct)DNA, circulating miRNA circulating RNA.  They also profile of single cells including CTCs (see Carter et al Nature Medicine 2017) and immune cells (with TIIML). This team is currently profiling ctDNA for patients entering the Christie Hospital Phase I trials unit to assist trial selection (see Rothwell et al Nature Medicine 2019), and enumerating and profiling ‘early’ circulating tumour cells 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 and provide upfront statistical support to study designs (see Kim et al Bioinformatics 2019).

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.

Selected Publications

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.
Pulmonary venous circulating tumor cell dissemination before tumor resection and disease relapse.
Nature Medicine [Epub 7 October 2019] 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

Lallo A, Gulati S, Schenk MW, Khandelwal G, Berglund UW, Pateras IS, Chester CPE, Pham TM, Kalderen C, Frese KK, Gorgoulis VG, Miller C, Blackhall F, Helleday T, Dive C. (2019)
Ex vivo culture of cells derived from circulating tumour cell xenograft to support small cell lung cancer research and experimental therapeutics.
British Journal of Pharmacology 176(3):436-450. PubMed abstract

Jayson GC, Zhou C, Backen A, Horsley L, Marti-Marti K, Shaw D, Mescallado N, Clamp A, Saunders MP, Valle JW, Mullamitha S, Braun M, Hasan J, McEntee D, Simpson K, Little RA, Watson Y, Cheung S, Roberts C, Ashcroft L, Manoharan P, Scherer SJ, Del Puerto O, Jackson A, O'Connor JPB, Parker GJM, Dive C. (2018)
Plasma Tie2 is a tumor vascular response biomarker for VEGF inhibitors in metastatic colorectal cancer.
Nature Communications 9(1):4672. PubMed abstract

Lallo A, Frese KK, Morrow CJ, Sloane R, Gulati S, Schenk MW, Trapani F, Simms N, Galvin M, Brown S, Hodgkinson CL, Priest L, Hughes A, Lai Z, Cadogan E, Khandelwal G, Simpson KL, Miller C, Blackhall F, O'Connor MJ, Dive C. (2018)
The Combination of the PARP inhibitor Olaparib and the WEE1 inhibitor AZD1775 as a new therapeutic option for small cell lung cancer.
Clinical Cancer Research 24(20):5153-5164. 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 Communication 7:13322. PubMed abstract

Girotti MR, Gremel G, Lee R, Galvani E, Rothwell D, Viros A, Mandal AK, Lim KH, Saturno G, Furney SJ, Baenke F, Pedersen M, Rogan J, Swan J, Smith M, Fusi A, Oudit D, Dhomen N, Brady G, Lorigan P, Dive C, Marais R. (2016)
Application of Sequencing, Liquid Biopsies, and Patient-Derived Xenografts for Personalized Medicine in Melanoma.
Cancer Discovery 6(3):286-99. PubMed abstract

Valle JW, Wasan H, Lopes A, Backen AC, Palmer DH, Morris K, Duggan M, Cunningham D, Anthoney DA, Corrie P, Madhusudan S, Maraveyas A, Ross PJ, Waters JS, Steward WP, Rees C, Beare S, Dive C, Bridgewater JA. (2015)
Cediranib or placebo in combination with cisplatin and gemcitabine chemotherapy for patients with advanced biliary tract cancer (ABC-03): a randomised phase 2 trial.
Lancet Oncology 16(8):967-78. 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