Genomic Instability as a Therapeutic Target in Breast and Colorectal Cancer

Lead Research Organisation: Imperial Cancer Research Fund
Department Name: London Research Institute (LIF)

Abstract

Genetic information is contained in units of DNA in a cell called chromosomes. Normal cells rely upon checkpoints to control the passage of genetic information contained in chromosomes to daughter cells. The mitotic checkpoint, regulates the passage of genetic information before the formation of daughter cells and if this fails, cancers become resistant to death induced by the taxane breast cancer drug and develop resistance to other cancer drugs in the laboratory. Failure of the same checkpoint promotes gain or loss of whole chromosomes (called chromosomal instability, CIN cancers) associated with worse prognosis in cancer patients.

Many patients with breast cancer experience side effects but derive limited or no benefit from taxane treatment. A CR-UK team will analyse breast cancer tissue from patients treated with taxanes within clinical trials to assess whether CIN is associated with taxane resistance. This may identify which patients may benefit from this treatment in the future.

The CRUK team will identify how to selectively target CIN cancers to promote new approaches for anticancer drug discovery. These drugs may eventually limit the evolution of tumour drug resistance and have greater cancer-specificity, reducing side effects to normal tissue (skin, hair and white blood cells) with normal chromosome number.

Technical Summary

Chromosomal instability (CIN) is associated with the acquisition of drug resistance and poorer prognosis in many solid tumours. Our work has focussed on the association of CIN with taxane resistance. We have identified several genes which when silenced by RNA interference (RNAi), impair a taxane induced mitotic arrest and promote paclitaxel resistance. Many of these genes promote centrosomal amplification, multinucleation and endoreduplication without drug exposure, indicating that aberrations in chromosomal segregation may serve as a marker of intrinsic taxane resistance. In agreement, we have established a correlation between increasing numerical-CIN (known as Chromosomal Numerical Heterogeneity or CNH) in breast and colorectal cancer cell lines and resistance to microtubule stabilising agents such as paclitaxel. The polygenic nature of multi-drug resistance, supported by our work, may explain the evolution of resistance to non-cross resistant cytotoxics in human tumours driven by genomic instability mechanisms such as CIN. Identifying vulnerable pathways within tumours harbouring specific patterns of genomic instability such as CNH may reveal novel oncogenic targets, enhance taxane sensitivity and limit the acquisition of multi-drug resistant disease.

Aims and Objectives
1. Assess the relationship between CNH and microtubule stabiliser response in breast and colorectal cancer.

2. Elucidate mechanisms of cancer cell survival in the presence of specific patterns of genomic instability (chromosomal or microsatellite instability) to:
provide therapeutic cancer-specific targets
limit acquisition of taxane and multi-drug resistant disease.

Design and Methodology
Using established clinical trial samples in primary breast cancer (NeoTango) and FISH expertise, the association of CNH status with paclitaxel response will be assessed in vivo and a gene expression signature associated with CNH derived.
A high throughput whole genome RNAi screen and an automated Acumen laser scanning cytometer will identify genomic instability-specific survival regulators in isogenic cancer cell lines deficient in mismatch repair or spindle assembly checkpoint components.
Expression of validated candidates will be assessed in breast and colorectal cancer trial samples (CINATRA, TACT, NeoTANGO) for which genomic instability data will be available. Live cell microscopy will elucidate the mechanisms of death following silencing of CIN-survival candidate genes.

Scientific and Medical Opportunities
Validated candidates may further understanding of mitotic deregulation and chromosome segregation in colorectal and breast cancer and provide suitable leads for future drug discovery programmes to delay multi-drug resistance by targeting specific mechanisms of genomic instability. This work may optimise the selection of patients with disease sensitive to microtubule inhibitors and provide therapeutic targets in taxane-resistant disease.

Publications

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A'Hern RP (2013) Taxane benefit in breast cancer--a role for grade and chromosomal stability. in Nature reviews. Clinical oncology

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Abbosh C (2018) Circulating tumour DNA analyses reveal novel resistance mechanisms to CDK inhibition in metastatic breast cancer. in Annals of oncology : official journal of the European Society for Medical Oncology

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Azim HA (2013) Utility of prognostic genomic tests in breast cancer practice: The IMPAKT 2012 Working Group Consensus Statement. in Annals of oncology : official journal of the European Society for Medical Oncology

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Burrell RA (2014) The evolution of the unstable cancer genome. in Current opinion in genetics & development

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Burrell RA (2014) Response to Bakhoum et al. in Current biology : CB

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Crockford A (2014) Implications of intratumour heterogeneity for treatment stratification. in The Journal of pathology

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Di Leo A (2015) New approaches for improving outcomes in breast cancer in Europe. in Breast (Edinburgh, Scotland)

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Gerlinger M (2013) Acquired resistance to crizotinib from a mutation in CD74-ROS1. in The New England journal of medicine

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Gerlinger M (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. in The New England journal of medicine

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Roylance R (2011) Relationship of extreme chromosomal instability with long-term survival in a retrospective analysis of primary breast cancer. in Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology

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Swanton C (2014) Deciphering root causes of intrinsic BRAF inhibitor resistance in melanoma: ushering in a new genomics case reports feature for Annals of Oncology. in Annals of oncology : official journal of the European Society for Medical Oncology

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Swanton C (2018) Cancer therapeutics through an evolutionary lens. in Journal of the Royal Society of Medicine

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Swanton C (2009) Chromosomal instability determines taxane response. in Proceedings of the National Academy of Sciences of the United States of America

 
Description St Georges House NHS Public Policy Review
Geographic Reach National 
Policy Influence Type Influenced training of practitioners or researchers
 
Description Breast Cancer Research Foundation
Amount $247,000 (USD)
Organisation The Breast Cancer Research Foundation 
Sector Charity/Non Profit
Country United States
Start 09/2015 
 
Description Cancer Research UK BIDD Genomics Grant
Amount £200,000 (GBP)
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2011 
End 01/2012
 
Description Cancer Research UK Scientific Executive Board
Amount £11,800,000 (GBP)
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2014 
End 01/2019
 
Description ERC Consolidator grant
Amount € 2,000,000 (EUR)
Organisation European Research Council (ERC) 
Sector Public
Country European Union (EU)
Start 06/2014 
End 06/2019
 
Description PREDICT Predicting individual response and resistance to VEGFR/mTOR pathway therapeutic intervention using biomarkers discovered through tumour functional genomics (5.8m euros across 11 participants)
Amount £1,500,000 (GBP)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 01/2011 
End 01/2014
 
Description Prostate Cancer Foundation
Amount $1,000,000 (USD)
Organisation Prostate Cancer Foundation 
Sector Charity/Non Profit
Country Global
Start 01/2012 
 
Description RESPONSIFY
Amount £600,000 (GBP)
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 01/2012 
End 01/2015
 
Description Rosetrees Trust
Amount £390,000 (GBP)
Organisation Rosetrees Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2013 
End 01/2016
 
Description TRACERx Grant award
Amount £11,800,000 (GBP)
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2014 
End 01/2023
 
Title Functional Metagene Approach to Accelerate Biomarker Discovery in Cancer Medicine 
Description We have published a method demonstrating that RNA interference techniques can be used to identify genes expressed in tumours that are predictive of drug response in patients with primary breast cancer. 
Type Of Material Data analysis technique 
Provided To Others? No  
Impact This has led to many invited lectures at Personalised Medicines conferences including NCRI and ESMO 2011 and a Harvard personalised medicines conference in 2010. There has also been significant interest from the Pharmaceutical industry about our predictive biomarker discovery methodologies with emerging collaborations with Roche, Novartis and Pfizer. 
 
Description PLOIDYNET Consortium 
Organisation Netherlands Cancer Institute (NKI)
Country Netherlands 
Sector Academic/University 
PI Contribution Bioinformatic analysis of aneuploid tumours
Collaborator Contribution analysis of tracerx lung tumour samples and their aneuploid nature
Impact none yet
Start Year 2015
 
Description PREDICT Consortium 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Myself and the research team were the first to demonstrate that RNA interference screening datasets could be used to predict paclitaxel response in breast cancer. This approach led my group to initiate the PREDICT Consortium (www.predictconsortium.eu) which was awarded a 5.8 million euro EU FP7 grant in Jan 2011.
Impact 1 paper in submission with the NEJM in the second round of review. Mulit-disciplinary collaboration between clinical trial centres in Europe and Cancer Research UK and the Royal Marsden Hospital. Funded by the European Union Framework Program 7 (5.8 million Euro grant over 3 years).
Start Year 2011
 
Description RESPONSIFY EU FP7 Consortium 
Organisation German Breast Group (GBG)
Country Germany 
Sector Charity/Non Profit 
PI Contribution I am a joint applicant on this grant to identify response biomarkers to anti-her2 and anti-angiogenic therapies in breast cancer,
Collaborator Contribution Derive rna interference screening approaches to identify molecular regulators of drug sensitivity.
Impact none yet, grant just commenced
Start Year 2011
 
Description TRACERx Consortium 
Organisation Cancer Research UK
Department Manchester Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution I am the chief investigator for this study.
Collaborator Contribution My colleagues Caroline Dive (Circulating tumour cells) and Dr Jacqui Shaw (circulating free DNA) are providing the circulating biomarker expertise for this study. My clinical colleagues at 5 national ECMC's are providing the patient material to work on for this cancer evolution study.
Impact Spatial and temporal diversity in genomic instability processes defines lung cancer evolution. de Bruin EC, McGranahan N, Mitter R, Salm M, Wedge DC, Yates L, Jamal-Hanjani M, Shafi S, Murugaesu N, Rowan AJ, Grönroos E, Muhammad MA, Horswell S, Gerlinger M, Varela I, Jones D, Marshall J, Voet T, Van Loo P, Rassl DM, Rintoul RC, Janes SM, Lee SM, Forster M, Ahmad T, Lawrence D, Falzon M, Capitanio A, Harkins TT, Lee CC, Tom W, Teefe E, Chen SC, Begum S, Rabinowitz A, Phillimore B, Spencer-Dene B, Stamp G, Szallasi Z, Matthews N, Stewart A, Campbell P, Swanton C. Science. 2014 Oct 10;346(6206):251-6. doi: 10.1126/science.1253462 Tracking genomic cancer evolution for precision medicine: the lung TRACERx study. Jamal-Hanjani M, Hackshaw A, Ngai Y, Shaw J, Dive C, Quezada S, Middleton G, de Bruin E, Le Quesne J, Shafi S, Falzon M, Horswell S, Blackhall F, Khan I, Janes S, Nicolson M, Lawrence D, Forster M, Fennell D, Lee SM, Lester J, Kerr K, Muller S, Iles N, Smith S, Murugaesu N, Mitter R, Salm M, Stuart A, Matthews N, Adams H, Ahmad T, Attanoos R, Bennett J, Birkbak NJ, Booton R, Brady G, Buchan K, Capitano A, Chetty M, Cobbold M, Crosbie P, Davies H, Denison A, Djearman M, Goldman J, Haswell T, Joseph L, Kornaszewska M, Krebs M, Langman G, MacKenzie M, Millar J, Morgan B, Naidu B, Nonaka D, Peggs K, Pritchard C, Remmen H, Rowan A, Shah R, Smith E, Summers Y, Taylor M, Veeriah S, Waller D, Wilcox B, Wilcox M, Woolhouse I, McGranahan N, Swanton C. PLoS Biol. 2014 Jul 8;12(7):e1001906.
Start Year 2014
 
Description 3 visits: Fund raisers: CR-UK; Patient relatives 
Form Of Engagement Activity Participation in an open day or visit at my research institution
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Results and Impact We have led 3 sessions in my laboratory demonstrating our MRC funded research activity to laypersons (high networth individuals /or patient relatives/or CR-UK fundraisers).

A great deal of interest was raised by our group. The Bobby Moore Foundation have returned for a further educational/promotional visit as a result of our first demonstration. A family of a patient has donated £7000 to my research team.
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Results and Impact x
Year(s) Of Engagement Activity 2017