Cancer - Recent Highlights

Lung cancer and mechanisms of polygenic risk

We are developing critical mass in the area of lung cancer with a focus on early diagnosis. Our hypothesis is that individual polygenic differences in airway response to smoke injury influence risk of lung cancer and COPD.

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We are developing critical mass in the area of lung cancer with a focus on early diagnosis. Our hypothesis is that individual polygenic differences in airway response to smoke injury influence risk of lung cancer and COPD. To explore this we are developing new gene regulatory network based approaches to understand polygenic susceptibility.  A Cambridge / Manchester/UCL collaboration is collecting the necessary airway (bronchial, buccal, nasal) samples from volunteers and patients. Meanwhile we have used our existing extensive samples and data from breast cancer to establish proof of principle for our methods. We have shown that : (a) the ‘top hit’ FGFR2 variant has perturbs the estrogen receptor network (Fletcher et al Nat. Commun 2013); (b) the differentially expressed genes on FGFR2 signalling are significantly enriched among the top GWAS loci; (c) genes related to the top breast GWAS loci are clustered within a group of regulons centred on ESR 1/ FOX A1 (in preparation). These results show that our network based approach provides new insights into polygenic mechanisms and that the heterogeneity of mechanisms is less than feared.

March 2014


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Breast & Ovarian Cancer

The breast BRC programme has remained extremely productive, with a total of 38 publications in the period Aug 2012-Feb 2014. These include 2 in Nature, one in New England Journal of Medicine, 3 in Lancet Oncology, 2 in Science Translational Medicine, 2 in the Journal of the National Cancer...

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Carlos Caldas, James Brenton, Helena Earl, Charlotte Coles

The breast BRC programme has remained extremely productive, with a total of 38 publications in the period Aug 2012-Feb 2014. These include 2 in Nature, one in New England Journal of Medicine, 3 in Lancet Oncology, 2 in Science Translational Medicine, 2 in the Journal of the National Cancer Institute and one in Journal of Clinical Oncology.

The work is broad and of high translational impact with highlights including:

(i) Imaging (Radiology) (M. Wallis, K. Taylor): Continued development of better screening with imaging.  (ii) Translational and experimental therapeutic trials (H. Earl, C. Caldas): Practice-changing observation that taxanes preceding anthracyclines result in higher rates of pathCR.  (iii) Radiotherapy research (C. Coles): Practice-changing demonstration of improved cosmetic results with breast IMRT.  (iv) Pharmacogenetics research (C. Caldas, P. Pharoah): Largest study to date on germline polymorphisms and taxane-induced neuropathy.  (v) Novel biomarkers, prognostic and predictive indices and molecular pathology (C. Caldas, E. Provenzano, H. Earl, P. Pharoah): Predictive impact of breast cancer subtyping in relation to anthracyclines; prognostic impact of miRNAs and demonstration of clinical validity of CTCs and ctDNA in metastatic breast cancer; demonstration of use of ctDNA exome sequencing to identify resistance-associated mutations.

March 2014


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Cambridge Cancer Trials Centre

Over the last 7 years, the Cambridge Cancer Trials Centre (CCTC) has evolved from an efficient recruiter to late phase trials led predominantly from outside Cambridge into a trials unit focused increasingly on Cambridge-led early phase and translational research.

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Duncan Jodrell, Tim Eisen

Over the last 7 years, the Cambridge Cancer Trials Centre (CCTC) has evolved from an efficient recruiter to late phase trials led predominantly from outside Cambridge into a trials unit focused increasingly on Cambridge-led early phase and translational research.  15% of open trials are phase I, phase I/II or experimental medicine, compared with 8% of the trials in follow-up. We have achieved this whilst remaining the country’s top ranked cancer research network for recruitment to NIHR portfolio studies (RCT (15.3%) and all trials (58.1%) expressed as a proportion of cancer incidence.  The importance of the CCTC to the BRC is two-fold: first, it enables early phase and translational studies to be performed and second, it facilitates the identification and recruitment of large numbers of patients to BRC-related studies.  The appointment in 2011 of 3 academic consultant positions, each with a 50% commitment to the Early Phase Clinical Trials Team (EPCTT) and a 50% commitment to specific cancers (breast, pancreas and prostate), has led to a phase of rapid expansion, currently including 11 open studies (4 Phase 1 (FIM), 6 Phase 1 combination, 1 biomarker studies), but with 16 further studies in set-up or development, including studies of 13C-hyperpolarised MRIS.  The BRC directly supports 2 research nurses in the EPCTT and funding to other cross cutting themes (e.g. tissue bank) supports these studies. The EPCTT prioritises Investigator Initiated Trials (IITs), based on “Cambridge science”, designed and led by the EPCTT, and IITs where Cambridge is inputting significant translational elements (e.g. imaging or genomics). It is planned to expand the EPCTT to our other priority areas (eg haematological malignancies) when funding permits.

March 2014


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Oesophageal Cancer

Cambridge continues to play a leading role in the oesophageal ICGC (International Cancer Genome Consortium) project to perform whole genome sequencing of oesophageal adenocarcinoma continues very successfully.

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Rebecca Fitzgerald's team

Cambridge continues to play a leading role in the oesophageal ICGC (International Cancer Genome Consortium) project to perform whole genome sequencing of oesophageal adenocarcinoma continues very successfully.

The bulk of the 200 cases sequenced so far have come from Cambridge with BRC support for tissue collection, pathology processing and QC. These data are enabling a comprehensive catalogue of mutations to be assembled. Analysis of recurrent mutations in samples of different stage of Barrett's dysplasia is allowing us to identify mutation timing and understand which mutations drive progression from pre-invasive diseases to cancer. In parallel to large-scale genomics analyses we are performing functional analyses on novel genes of interest and have shown that amplification of TRIM44 may serve as a biomarker for the likelihood of patients with oesophageal cancer responding to mTOR inhibitor therapy.

We have continued to develop our novel diagnostic test for Barrett’s oesophagus called the Cytosponge. A case control trial on over 1,200 patients comparing the Cytopsonge and endoscopy has just been completed - all procedures in Cambridge were conducted in the BRC supported Clinical Investigation Ward. The technology has now been licensed to Covidien.

March 2014

 


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Haematological Malignancies

BRC funding primarily supports the Blood and Stem Cell Biobank (BSB) which undertakes processing and banking of peripheral blood and bone marrow cells from patients with a wide variety of haematological malignancies, together with cord blood cells.

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Haematological malignancies (Green, Huntly, Gottgens, Warren, Du, Campbell, Vasilliou, Chapman). 

BRC funding primarily supports the Blood and Stem Cell Biobank (BSB) which undertakes processing and banking of peripheral blood and bone marrow cells from patients with a wide variety of haematological malignancies, together with cord blood cells.  Banked samples support multiple research programs in the university and neighbouring institutes (eg Sanger and Babraham Institutes).  Since April 2012 the above groups have published over 30 BRC-supported papers in journals that include New England Journal of Medicine, Nature, Nature Methods, Cell Stem Cell, Cell Reports, PLoS Biology and J Clin Invest.

Myeloid malignancies, and their relationship to normal haematopoiesis, remain a major focus. Selected highlights which have depended on BSB samples include: (i) the Green and Campbell groups have described the genomic landscape of 151 patients with myeloproliferative neoplasms (MPNs) and identified CALR as a new cancer gene, thus identifying an unexpected link between endoplasmic reticulum biology and tumorigenesis (Nangalia et al NEJM 2013); the Green group has also described a new mechanism associated with acquired chromosome deletions (Aziz et al J Clin Invest 2013), demonstrated for the first time the consequences for single stem cells of expressing an oncogene associated with human malignancy (Kent PLoS Biol 2013), and has continued to illuminate the pathogenesis and management of the MPNs (eg Campbell et al Blood 2012; Godfrey et al Blood 2012; Hobbs et al Blood 2013) ; (ii) the Gottgens lab has developed compendia of genome-scale transcription factor binding maps for normal and leukaemic blood cells (Ruau et al, Nature Methods 2013) as well as embryonic stem cells (Martello et al, Cell Stem Cell. 2012); (iii) the Huntly group has identified BET proteins as therapeutic targets in AML (Dawson et al NEJM 2012) and is about to start a multinational multicentre first Phase I trial (with GSK) of a BET inhibitor in relapsed and refractory haematological malignancies; (iv) the Warren lab has shown that the USB1 protein mutated in a leukaemia predisposition disorder (poikiloderma with neutropenia) is required for the biogenesis and processing of spliceosomal U6 small nuclear RNA, thus linking the pathogenesis of inherited and acquired forms of myelodysplasia to splicing defects. (Hilcenko et al Blood 2013).  We are also strengthening the area of lymphoid malignancies with the recruitment of Chapman working on RNA binding proteins in the pathogenesis of myeloma, and Ringshausen, who is due to arrive Summer 2014, and who will work on tumour/microenvironment interactions in CLL.


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Prostate Cancer

We continue to work on how the androgen receptor (AR) regulates prostate cell growth in man.

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David Neal's group

We continue to work on how the androgen receptor (AR) regulates prostate cell growth in man. There have been several recent advances: (a) we have performed a comprehensive analysis of AR binding sites and associated genes in primary human prostate cancer tissues, including castrate-resistant prostate cancer (CRPC) (Sharma et al Cancer Cell 2103); we identified a 16 gene signature that outperformed a larger in-vitro-derived signature in clinical data sets, showing the importance of persistent AR signalling in CRPC, and confirming the critical importance of studying human cancer material; (b) we demonstrated that Hes6 is a key transcriptional co-factor up-regulated in aggressive human prostate cancer (Whitaker et al Oncogene 2013) - a Hes6-associated signature predicts poor outcome in prostate cancer, and can be pharmacologically targeted; (c) we demonstrated that over-expression of N-acetyl-L-aspartyl-L-glutamate peptidase-like 2 (NAALADL2) is associated with stage and grade and predicts poor survival following radical prostatectomy (Ramos-Montoya et al EMBO Mol Med In press).

March 2014


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