Translational approaches to improving cancer screening and diagnosis

Lead Research Organisation: MRC Cancer Cell Unit

Abstract

As we understand more about how tumours arise, it should be possible to devise better strategies to diagnose and treat cancer. We are aiming to develop more effective ways to detect common malignancies, through an understanding of the biology of cancer cells. We are currently analysing a test that we have developed to improve diagnosis of cancers at a number of sites in the body, including cervix, mouth and bowel. For the first two cancers we are working in collaboration with colleagues in Bangalore, India. In addition, we are investigating the mechanisms by which some types of human papillomavirus, the wart virus, cause cancer in the genital tract, particularly the cervix. We are studying the process by which fragments of the virus are inserted into the DNA of infected cells, as well as the significance of changes in the levels of cellular genes that are associated with the development of malignancy. This work may lead to methods to predict how aggressive a particular tumour will be, so that each patient receives neither too little nor too much treatment, and may also suggest new strategies for treating the disease.

Technical Summary

We aim to: (i) use minichromosome maintenance proteins (MCMs) as biomarkers to improve cancer screening and (ii) study mechanisms of human papillomavirus (HPV)-associated carcinogenesis, in order to develop more effective prognostic and therapeutic interventions for cervical cancer, an epithelial malignancy of major global importance. We demonstrated the clinical value of MCM immunocytochemistry in improving the early detection of several common malignancies, including cervical, colorectal and lung cancer. The first clinical product is now in use internationally and a second generation version is in major FDA trials. We use a unique preclinical model of HPV-related carcinogenesis, validated through a large tissue resource, to study relationships between viral and host factors in the early stages of the cervical metaplasia-dysplasia-carcinoma sequence. As part of this work we discovered the role of two genes that are frequently over-expressed in cervical cancers and will study the potential of one of these, the cytokine receptor OSMR, to act as a cell surface target for antibody-based inhibition. We will further investigate the mechanisms by which HPV oncogene expression is deregulated during cervical carcinogenesis and study the significance of viral physical state (episomal vs. integrated) and site of integration into the host genome, as well as mechanisms of HPV persistence in cervical epithelial cells. We aim to develop new tools for diagnosis and treatment at different stages in the lengthy progression sequence from HPV infection to malignancy. Important clinical benefits of this work will be reduced morbidity and costs associated with over-treatment of non-progressive cervical pre-cancers and improved therapeutic options in cervical carcinomas, particularly early-stage disease.

Publications

10 25 50
 
Description Cancer Research UK Science Plan Review: Biomarkers.
Geographic Reach National 
Policy Influence Type Participation in a national consultation
 
Description Experimental Cancer Medicine Centres (ECMC) Steering Group: Standardisation of analysis and reporting of circulating miRNAs by RTqPCR
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
 
Description Addenbrooke's Charity, Project Grant
Amount £56,517 (GBP)
Organisation Addenbrooke's Charitable Trust (ACT) 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2012 
End 01/2013
 
Description Addenbrookes Charity, Consumables Grant
Amount £45,781 (GBP)
Organisation Addenbrooke's Charitable Trust (ACT) 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2006 
End 01/2007
 
Description Amgen Studentship scheme
Amount £2,000 (GBP)
Organisation Amgen Inc 
Sector Private
Country United States
Start 07/2010 
End 09/2010
 
Description Assessing the clinical utility of blood-based microRNAs for the management of malignant germ cell tumours
Amount £32,611 (GBP)
Organisation University of Cambridge 
Department Isaac Newton Trust
Sector Academic/University
Country United Kingdom
Start 02/2016 
End 01/2018
 
Description CLIC Sargent Project Grant
Amount £79,960 (GBP)
Organisation CLIC Sargent 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2006 
End 01/2009
 
Description CRUK Project Grant
Amount £14,223 (GBP)
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2007 
End 01/2008
 
Description CRUK Project Grant
Amount £10,000 (GBP)
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2007 
End 01/2008
 
Description Children with Cancer UK project grant
Amount £148,000 (GBP)
Organisation Children with Cancer UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2014 
End 10/2017
 
Description Children with Cancer UK project grant
Amount £99,840 (GBP)
Organisation Children with Cancer UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2012 
End 01/2014
 
Description Cytosystems Collaborative Project Grant
Amount £8,000 (GBP)
Organisation Cytosystems Ltd 
Sector Private
Country United Kingdom
Start 01/2009 
End 01/2010
 
Description Improving Outcomes for Children and Young Adults with Extracranial Germ Cell Tumours
Amount $2,300,000 (USD)
Funding ID RG79925 
Organisation St. Baldrick's Foundation 
Sector Charity/Non Profit
Country United States
Start 02/2016 
End 01/2021
 
Description Institute of Cancer - Kavragiilidou
Amount £23,186 (GBP)
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2007 
End 10/2010
 
Description MRC Clinical Training Fellowship
Amount £230,961 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2008 
End 01/2011
 
Description MRC Clinical Training Fellowship - Murray
Amount £230,968 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2009 
End 12/2011
 
Title Archive of cervical squamous cancers and pre-cancers 
Description In collaboration with Kidwai Institute, India and University of Aberdeen, we have obtained a collection of cervical squamous cell carcinomas and squamous intraepithelial lesions (n=~70). We have systematically characterised global changes in genomic DNA, messenger RNA and microRNA levels, and are currently examining relationships between the data sets, in collaboration with bioinformatics colleagues in Cambridge. 
Type Of Material Biological samples 
Year Produced 2006 
Provided To Others? Yes  
Impact Improved understanding of the biology of cervical squamous cell neoplasia. 
 
Title UK archive of paediatric malignant germ cell tumours 
Description With the approval of the Children's Cancer and Leukaemia Group, we obtained the entire UK collection of paediatric malignant germ cell tumours (n=120). We have systematically characterised global changes in genomic DNA, messenger RNA and microRNA levels, and are currently examining relationships between the data sets, in collaboration with bioinformatics colleagues in Cambridge. 
Type Of Material Biological samples 
Year Produced 2006 
Provided To Others? Yes  
Impact Improved understanding of the biology of malignant germ cell tumours in children, including the differences that expalin differences in clinical behaviour compared to equivalent tumours in adults. 
 
Title W12 cell line 
Description W12 cell line, a model of cervical carcinogenesis. W12 is a non-clonal cell culture, propagated from a cervical low-grade squamous intraepithelial lesion (LSIL) that arose following natural cervical infection with HPV16, which represents a unique system for studying early events in HPV-associated carcinogenesis. At early passages, Southern blotting reveals approximately 100 human papillomavirus type 16 (HPV16) episomes per cell, with no detectable integrants, and the cells recapitulate an LSIL in organotypic tissue culture. Long term in vitro culture series are characterised by spontaneous clearance of episomes and the emergence of cells containing integrated HPV16, with different integrants being selected in different culture series. These changes are associated with the development of high level genomic instability and phenotypic progression through high-grade SIL to squamous cell carcinoma. 
Type Of Material Cell line 
Year Produced 2006 
Provided To Others? Yes  
Impact W12 is acknowledged as the only cell line system in the world that accurately models cervical carcinogenesis following natural infection with HPV16. 
 
Title Pipeline for robust serum microRNA detection/analysis in malignant germ cell tumours 
Description Published in BJC in 2016 - details included in manuscript (PMID 26671749) 
Type Of Material Data analysis technique 
Year Produced 2016 
Provided To Others? Yes  
Impact Interest from other national and international research groups to replicate our model/pipeline 
 
Title swatCGH 
Description Sliding windows adaptive thresholds CGH is an automated array comparative genomic hybridisation analysis software written in R for Linux / Unix and incorporating distributed processing with condor middleware. Roberts I, Carter SA, Scarpini CG, Karagavriilidou K, Barna JC, Calleja M, Coleman N (2012) A high throughput computational framework for identifying significant copy number aberrations from array comparative genomic hybridisation data Advances in Bioinformatics 2012:876976 
Type Of Material Computer model/algorithm 
Year Produced 2012 
Provided To Others? Yes  
Impact We have developed an R based strategy to region of interest detection. swatCGH is a BASH wrapper to R and condor camgrid. It automates the process of sending the array data to condor camgrid. It manages the linking to snapCGH for preprocessing, undertaking region analysis with custom functions, and returning the results in a manageable web style format. 
URL http://www.path.cam.ac.uk/research/investigators/coleman/swatCGH/004.html
 
Description Beckton Dickinson, Global 
Organisation Becton, Dickinson and Company
Country United States 
Sector Private 
PI Contribution Development of MCM technology for FDA approval.
Collaborator Contribution Research discussionsresearch discussions
Impact Development of MCM technology for FDA approval.
 
Description Beckton Dickinson, Global 
Organisation Becton, Dickinson and Company
Country United States 
Sector Private 
PI Contribution Development of MCM technology for FDA approval.
Collaborator Contribution Research discussionsresearch discussions
Impact Development of MCM technology for FDA approval.
 
Description Development of MCM technology for bladder cancer screening 
Organisation Cytosystems Ltd
Country United Kingdom 
Sector Private 
PI Contribution Research discussions
Collaborator Contribution Research discussions
Impact Development of MCM technology for FDA approval.
Start Year 2006
 
Description Geeta Mukherjee 
Organisation University of California, San Diego (UCSD)
Department Department of Pathology
Country United States 
Sector Academic/University 
PI Contribution Exchange of research resources knowledge
Collaborator Contribution Exchange of research resources knowledge
Impact PubMed ID- 17516585, 17471471, 17342084
Start Year 2006
 
Description Margaret Stanley 
Organisation University of Cambridge
Department Department of Pathology
Country United Kingdom 
Sector Academic/University 
PI Contribution Exchange of knowledge and research methods
Collaborator Contribution Exchange of knowledge and research methods
Impact PubMed ID- 19645010, 19035938, 18652663, 18413654, 17642065, 16973673, 16505361
 
Description VarleighDx 
Organisation VarleighDx
Country United Kingdom 
Sector Private 
PI Contribution Launch of a CE-marked test for early diagnosis of pancreatic cancer
Collaborator Contribution Commercialisation of MCM test
Impact Launch of a CE-marked test for early diagnosis of pancreatic cancer
Start Year 2016
 
Title Cancer Markers for prognosis and screening of anti-cancer agents 
Description Use of Drosha as marker of adverse outcome and as a potential therapeutic target in squamous cell carcinoma. 
IP Reference WO2008125883 
Protection Patent granted
Year Protection Granted 2008
Licensed No
Impact Ongoing research into mechanisms underlying the effects of Drosha over-expression.
 
Title Detection of dysplastic or neoplastic cells using anti-MCM2 antibodies 
Description Determination of cellular growth abnormality, particularly cancerous abnormality, by detection of target polypeptides or encoding mRNA, where the target polypeptides are members of the preinitiation complex of DNA replication in tissue, cells or fluid. Target polypeptides include CDC6, MCM2, MCM3, MCM4, MCM5, MCM6 and MCM7. Test samples include tissue of the cervix (both biopsy and smear samples), breast, colon, lung, bladder, skin, larynx, oesophagus, bronchus, lymph nodes and urinary tract (both biopsy and cytology smear samples), in determination of cancerous and precancerous cellular growth abnormality, and cells spun from urine, blood and serum, in determination of haematological malignancies and evidence of metastatic sarcoma and carcinoma. 
IP Reference US2003143646 
Protection Patent granted
Year Protection Granted
Licensed Yes
Impact Licenced to Beckton Dickinson and Cytosystems. Licencing income being received.
 
Title Substrate for holding an array of experimental samples 
Description A 3-dimensional substrate for improved packing density in microarrays, and for registering sample deposition. 
IP Reference  
Protection Protection not required
Year Protection Granted 2006
Licensed No
Impact Partnership with MiniFAB Pty Ltd, Victoria, Australia.
 
Title Cytosystems solution 
Description An MCM-based test for early detection of bladder cancer using cytology samples. 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2009
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Still in development by Cytosystems Ltd. 
 
Title ProExC 
Description A molecular test for early diagnosis of cervical cancer and pre-cancer in cytology and histology preparations. 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Wide-scale adoption
Year Development Stage Completed 2006
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Increasing use in US and elsewhere, both for intended use and off label use. 
 
Title SurePathPlus 
Description An MCM-based test for primary cervical screening. 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2009
Development Status On hold
Impact Currently on hold. 
 
Description Cambridge Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact Cancer screening part of the exhibit involve microscopes to compare Pap and MCM screening.

Increased understanding of cancer screening with MCM proteins.
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010
 
Description MRC Press release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Fighting HPV could help cervical cancer develop http://www.mrc.ac.uk/Newspublications/News/MRC003341

Increased profile.
Year(s) Of Engagement Activity 2006
 
Description MRC Press release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Spotting cancer quicker in developing countries http://www.mrc.ac.uk/Newspublications/News/MRC003623

Increased profile.
Year(s) Of Engagement Activity 2007
 
Description MRC Press release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Cambridge scientists discover an additional step along the road to cervical cancer http://www.mrc.ac.uk/Newspublications/News/MRC002008

Increased profile.
Year(s) Of Engagement Activity 2006
 
Description MRC Press release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Press release on screening for oral cancer. http://www.mrc.ac.uk/Newspublications/News/MRC001721

Increased profile.
Year(s) Of Engagement Activity 2007
 
Description MRC Showcase Oncology and Tumour Biology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Health professionals
Results and Impact Lecture entitled: New targets for improving the clinical management of cervical neoplasia.

Increased awareness of the work's clinical potential.
Year(s) Of Engagement Activity 2007
 
Description MRC press release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Press release on MRC website- A new 'smear test' to prevent anal cancer http://www.mrc.ac.uk/Newspublications/News/MRC004911

Increased profile
Year(s) Of Engagement Activity 2008
 
Description MRC press release 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Press interest following receipt of Medical Futures Innovation Award. Innovation honour for cancer cell scientists http://www.mrc.ac.uk/NewsViewsAndEvents/News/MRC003798

Widespread press coverage, increasing awareness of the work and its potential.
Year(s) Of Engagement Activity 2007
 
Description University of Cambridge Press Release - LIN28/let-7 axis in germ cell tumours 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Interest from media and reported in national press, August 2013

Increased correspondence from patient groups and other health care professionals re the potential for targetting this pathway therapeutically
Year(s) Of Engagement Activity 2014
URL http://www.cam.ac.uk/research/news/scientists-discover-a-molecular-switch-in-cancers-of-the-testis-a...