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Posts Tagged ‘London Research Institute’


Curator: Aviva Lev-Ari, PhD, RN

Dr. Charles Swanton, Cancer Research, UK’s London Research Institute explained in his March 29, 2013 interview for Science, that the cancer treatments often fail as a result of the increasing evidence that tumors contain a heterogeneous mix of cells – tissue tagged with colored fluorescent markers for specific molecular changes sh0ws that not all cells in a tumor are the same.

http://www.sciencemag.org SCIENCE vol 339, 3/29/2013, 1543-1545

His team sequenced DNA taken from different parts of a patient’s kidney tumor, the sequence of each part was different. Severaal genetic changes were shared throughout the original tumor mass and iother tumors, or metastases, most were present in only some parts, suggesting that tumors host diverse populations of cells. some of these cells may be resistant to a treatment and continue to grow.

The findings presented below from Swanton’s Lab and from Polyak’s Lab demonstrate that intra-tumor heterogeneity as revealed by genome sequencing applied as Multiregion Sequencing might suggest that the current best practice in Oncology, of a single biopsy, must be abandoned for the sake of a new and more promising practice of multiple biopsies of the same tumor.

Kornelia Polyak’s Lab at Dana-Farber Cancer Institute, dedicated to the molecular analysis of human breast cancer

http://polyaklab.dfci.harvard.edu/

Our goals are to:

  • Better understand the molecular evolution of human breast tumors
  • Use this knowledge to improve the clinical management of breast cancer patients

Project 1: Breast tumor evolution

Modeling clonal evolution in mouse xenograft models

Cancers develop as a result of somatic evolution. Deciphering the evolutionary dynamics behind this should provide a more accurate understanding of how cancers arise and enable more intelligent approaches toward anti-cancer therapies. However, this area receives almost no experimental attention, and our understanding of clonal evolution in cancers is very rudimentary. To address this deficiency, we have developed a mouse xenograft model of human breast cancers that allows us to follow dynamics of clonal competition in genetically heterogeneous tumors.

Intratumor heterogeneity and metastasis

Metastatic dissemination of cancer cells is the most prominent cause of death due to breast cancer. Recent work in this field has established that the progression of metastatic invasion from the primary tumor to distant locations (such as bone, lungs, and brain) depends on heterogeneous interactions of cancer cells with each other and with cells composing the microenvironment. We aim to elucidate some of the factors and mechanisms that influence metastatic co-operation between cancer cells and their environment in order to fully understand the metastatic cascade and aid in the development of therapies that address this phenomenon.

Diversity in human breast tumors

Intra-tumor genetic and phenotypic diversity may predict the risk of breast cancer progression and response to treatment. To deepen our understanding of these factors, we have been defining intra-tumor diversity using immuno-FISH and ecological models in breast tumors at different progression stages (i.e., in situ, invasive, metastatic), and before and after chemotherapy or targeted (e.g., antu-Her2) treatment.

Project 2: The role of the tumor microenvironment in breast cancer

Interrogating consequences of interactions between breast carcinoma cells and tumor fibroblasts

While it is becoming increasingly apparent that interactions between carcinoma cells and tumor stroma are an essential part of tumor biology, our understanding of this crosstalk is far from complete. Using organotypic 3D culture models, we are interrogating mutual changes in transcriptome, metabolome, and phospho-proteome that result from the interaction between breast carcinoma cells and primary breast tumor-associated fibroblasts.

Myoepithelial cells and leukocytes in DCIS

The progression from in situ to invasive carcinoma is a key but poorly understood step of breast tumorigenesis, characterized by loss of the myepithelial cell layer and basement membrane. We hypothesize that the differentiation of bipotential mammary epithelial progenitors to myoepithelial cells is progressively inhibited by signals coming from tumor epithelial cells and stromal cells, such as leukocytes, leading to their eventual disappearance. Project objectives include:

  • Defining normal myoepithelial cell differentiation and its abnormalities in DCIS
  • Characterizing the role of immune cells in myoepithelial cell differentiation during breast carcinoma progression using in vivo and in vitro model systems and human breast tissue

The completion of this project will increase our understanding of the role of myoepithelial and immune cells in breast cancer, and may also provide new targets for breast cancer treatment via abnormally expressed paracrine signaling in the tumor microenvironment.

Project 3: Epigenetics in breast cancer risk and tumor development

Pregnancy study

Human epidemiological and experimental data in rodent models suggest that full-term pregnancy in early adulthood decreases the risk of estrogen receptor positive (ER+) breast cancer in post-menopausal women; however, the underlying mechanism is largely unknown. We hypothesized that the cancer-preventive effects of parity may be due to alterations in the number or properties of mammary epithelial progenitor/stem cells that are thought to be the cell-of-origin of breast cancer, rendering them less susceptible to oncogenesis. To test this hypothesis, we analyzed the relative frequency and comprehensive molecular profiles of four distinct cell types (CD24+ luminal, CD10+ myoepithelial, lin-/CD24-/CD44+ progenitor-enriched, and stromal fibroblasts) isolated from normal breast tissue of premenopausal nulliparous and parous women. Based on the comprehensive analysis of gene expression, DNA, and histone H3 K27 trimethylation profiles of these cell types, we determined that the most significant changes occurred in lin-/CD24-/CD44+ progenitor-enriched cells. The activity of many genes and pathways involved in development, differentiation, and cell cycle regulation are decreased in parous women that may contribute to their decreased breast cancer risk. We also identified a parity-associated gene signature that predicted clinical outcome in breast cancer patients diagnosed with ER+ tumors.

The role of DNA methylation in mouse mammary gland development

The mouse mammary gland is a useful model system for understanding factors that regulate mammary development. We are pursuing molecular characterization of the different cell types that comprise the mammary epithelium of the mouse. Based on the varying proportional distributions we observe in the mature, progenitor, and stem cell populations of the mammary gland during different life stages, we seek to understand the underlying molecular cues that maintain cell type identities and direct cellular distribution changes by studying the gene expression and epigenetic properties of distinct cell populations during puberty and pregnancy, stages during which there is dramatic tissue remodeling in the mammary gland. Furthermore, with the use of in vitro and in vivo mouse models for the functional characterization of maintenance DNA methylation, we are characterizing potential active roles of this important epigenetic mark in directing cell fate in the mammary gland.

Histone modifying enzymes as new therapeutic targets

The differentiation of normal stem cells and the development of normal tissue are controlled by epigenetic mechanisms. Abnormalities in these processes play a role in the initiation and progression of tumors and intra-tumor diversification of cancer cells. A number of histone-modifying genes were found to be mutated in breast and other cancers, implying that these genes may represent novel therapeutic targets and biomarkers. We have recently reported the characterization of cell-type specific patterning of histone and DNA methylation in normal breast tissues. We developed modified chromatin immunoprecipitation combined with high-throughput sequencing (ChIP-Seq) protocol which enables us to investigate the epigenetic status genome-wide, using limited numbers of cells purified from human breast tissue samples. Currently, we are using various genomic profiling and functional studies to validate several histone demethylases as potential therapeutic targets in breast cancer.

Determinants of basal-like and luminal breast cancer cell phenotypes

Basal-like and luminal breast tumors have distinct molecular profiles and clinical behavior, yet the mechanisms underlying these differences are poorly defined. We investigated the potential role of genetic factors in determining these distinct phenotypes and their inheritance pattern by generating somatic cell fusions between basal-like and luminal breast cancer cells and analyzing their molecular profiles and functional characteristics. Based on the molecular profiles, we identified candidate key transcriptional and epigenetic determinants of basal-like and luminal cell phenotypes. We are further characterizing these genes using functional genomics approaches.

Project 4: Emerging therapeutic targets in breast cancer

Amplified kinases and novel targets in breast cancer

Kinase inhibitors have been one of the most successful drugs for cancer treatments, but their efficacies in patients are still not satisfactory. We have identified novel kinases amplified in breast cancer, and are using functional genomic approaches to validate them as therapeutic targets.

Novel therapeutic targets in triple negative breast cancer

We have conducted an shRNA cell viability screen of 1,576 candidate genes differentially expressed between CD44+CD24- stem cell-like and CD44-CD24+ more differentiated luminal breast cancer cells. These shRNA were further tested across 14 breast cancer cell lines, thereby generating a list of 15 genes of high interest as candidate therapeutic targets against CD44+CD24- cells, including IL6, CXCL3, PTGIS, IGFBP7, PFKFB3 and HAS1. We have followed up and validated the Il6/Jak2/Stat3 signaling pathway in further detail and demonstrated that JAK2 inhibitors may effectively inhibit the growth of breast tumors that have activation of this pathway as determined based on expression of phospho-Stat3 (pStat3). Based on our preclinical data, a clinical trial testing the efficacy of Jak2 inhibitors in pStat3+ breast tumors (enriched in BLBC) is being initiated at DFCI. More recently we also found that a high fraction of inflammatory breast cancer (IBC) are also positive for pStat3, and thus, may respond to JAK kinase inhibition. Besides the JAK/Stat3 pathway, other potentially promising targets include CXCR2, PTGIS, and HAS1. We are conducting preclinical studies validating these genes and their combination as potential new therapeutic strategies in breast cancer.

Swanton’s results was published in NEJM on March 8, 2012. 143 citations followed by year end.

http://www.med.upenn.edu/timm/documents/Minn_NEJMTimmMainarticle.pdf

Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

Marco Gerlinger, M.D., Andrew J. Rowan, B.Sc., Stuart Horswell, M.Math., James Larkin, M.D., Ph.D.,

David Endesfelder, Dip.Math., Eva Gronroos, Ph.D., Pierre Martinez, Ph.D., Nicholas Matthews, B.Sc.,

Aengus Stewart, M.Sc., Patrick Tarpey, Ph.D., Ignacio Varela, Ph.D., Benjamin Phillimore, B.Sc., Sharmin Begum, M.Sc.,

Neil Q. McDonald, Ph.D., Adam Butler, B.Sc., David Jones, M.Sc., Keiran Raine, M.Sc., Calli Latimer, B.Sc.,

Claudio R. Santos, Ph.D., Mahrokh Nohadani, H.N.C., Aron C. Eklund, Ph.D., Bradley Spencer-Dene, Ph.D.,

Graham Clark, B.Sc., Lisa Pickering, M.D., Ph.D., Gordon Stamp, M.D., Martin Gore, M.D., Ph.D., Zoltan Szallasi, M.D.,

Julian Downward, Ph.D., P. Andrew Futreal, Ph.D., and Charles Swanton, M.D., Ph.D.

Abstr act

From the Cancer Research UK London

Research Institute (M. Gerlinger, A.J.R.,

S.H., D.E., E.G., P.M., N.M., A.S., B.P.,

S.B., N.Q.M., C.R.S., B.S.-D., G.C., G.S.,

J.D., C.S.), Royal Marsden Hospital Department

of Medicine ( J.L., M.N., L.P.,

G.S., M. Gore), Wellcome Trust Sanger

Institute (P.T., I.V., A.B., D.J., K.R., C.L.,

P.A.F.), Barts Cancer Institute at the

Barts and the London School of Medicine

and Dentistry (M. Gerlinger), and the University

College London Cancer Institute

(C.S.) — all in London; the Technical University

of Denmark, Lyngby (A.C.E., Z.S.);

and Harvard Medical School, Boston (Z.S.).

Address reprint requests to Dr. Swanton at

the Cancer Research UK London Research

Institute, Translational Cancer Therapeutics

Laboratory, 44 Lincoln’s Inn Fields,

London WC2A 3LY, United Kingdom, or

at charles.swanton@cancer.org.uk.

Drs. Gerlinger, Larkin, Gronroos, Martinez,

and Swanton and Mr. Rowan, Mr. Horswell,

Mr. Endesfelder, Mr. Matthews, and

Mr. Stewart contributed equally to this

article.

N Engl J Med 2012;366:883-92.

Copyright © 2012 Massachusetts Medical Society.

Background

Intratumor heterogeneity may foster tumor evolution and adaptation and hinder

personalized-medicine strategies that depend on results from single tumor-biopsy

samples.

Methods

To examine intratumor heterogeneity, we performed exome sequencing, chromosome

aberration analysis, and ploidy profiling on multiple spatially separated samples obtained

from primary renal carcinomas and associated metastatic sites. We characterized

the consequences of intratumor heterogeneity using immunohistochemical analysis,

mutation functional analysis, and profiling of messenger RNA expression.

Results

Phylogenetic reconstruction revealed branched evolutionary tumor growth, with 63 to

69% of all somatic mutations not detectable across every tumor region. Intratumor

heterogeneity was observed for a mutation within an autoinhibitory domain of the

mammalian target of rapamycin (mTOR) kinase, correlating with S6 and 4EBP

phosphorylation in vivo and constitutive activation of mTOR kinase activity in vitro.

Mutational intratumor heterogeneity was seen for multiple tumor-suppressor genes

converging on loss of function; SETD2, PTEN, and KDM5C underwent multiple distinct

and spatially separated inactivating mutations within a single tumor, suggesting

convergent phenotypic evolution. Gene-expression signatures of good and poor prognosis

were detected in different regions of the same tumor. Allelic composition and

ploidy profiling analysis revealed extensive intratumor heterogeneity, with 26 of 30 tumor

samples from four tumors harboring divergent allelic-imbalance profiles and with

ploidy heterogeneity in two of four tumors.

Conclusions

Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape

portrayed from single tumor-biopsy samples and may present major challenges to

personalized-medicine and biomarker development. Intratumor heterogeneity, associated

with heterogeneous protein function, may foster tumor adaptation and therapeutic

failure through Darwinian selection. (Funded by the Medical Research Council

and others.)

n engl j med 366;10 nejm.org march 8, 2012

Sci Transl Med 28 March 2012:
Vol. 4, Issue 127, p. 127ps10
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3003854
  • PERSPECTIVE

TUMOR HETEROGENEITY

Intratumor Heterogeneity: Seeing the Wood for the Trees

  1. Timothy A. Yap1*,
  2. Marco Gerlinger2,3*,
  3. P. Andrew Futreal4,
  4. Lajos Pusztai5 and
  5. Charles Swanton2,6†

+Author Affiliations


  1. 1Department of Medicine, Royal Marsden NHS Foundation Trust, Downs Road, Sutton, Surrey SM2 5PT, UK.

  2. 2Translational Cancer Therapeutics Laboratory, Cancer Research UK London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3LY, UK.

  3. 3Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK.

  4. 4Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.

  5. 5Department of Breast Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

  6. 6University College London Cancer Institute, Huntley Street, London WC1E 6BT, UK.

  7. *These authors contributed equally to this work.
  1. Corresponding author. E-mail: charles.swanton@cancer.org.uk

ABSTRACT

Most advanced solid tumors remain incurable, with resistance to chemotherapeutics and targeted therapies a common cause of poor clinical outcome. Intratumor heterogeneity may contribute to this failure by initiating phenotypic diversity enabling drug resistance to emerge and by introducing tumor sampling bias. Envisaging tumor growth as a Darwinian tree with the trunk representing ubiquitous mutations and the branches representing heterogeneous mutations may help in drug discovery and the development of predictive biomarkers of drug response.

Citation: T. A. Yap, M. Gerlinger, P. A. Futreal, L. Pusztai, C. Swanton, Intratumor Heterogeneity: Seeing the Wood for the Trees. Sci. Transl. Med. 4, 127ps10 (2012).

THE EDITORS SUGGEST THE FOLLOWING RELATED RESOURCES ON SCIENCE SITE

In Science Translational Medicine

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    • Bert Vogelstein and
    • Kenneth W. Kinzler

    Sci Transl Med 28 March 2012 4:127ed2

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:

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  • A tale of two approaches: complementary mechanisms of cytotoxic and targeted therapy resistance may inform next-generation cancer treatmentsCarcinogenesis 1 April 2013 34:725-738
  • Intratumor heterogeneity in human glioblastoma reflects cancer evolutionary dynamicsProc. Natl. Acad. Sci. USA 5 March 2013 110:4009-4014
  • Accelerating Cancer Therapy Development: The Importance of Combination Strategies and Collaboration. Summary of an Institute of Medicine WorkshopClin. Cancer Res. 15 November 2012 18:6101-6109
  • Pluripotent Stem Cell-Based Cancer Therapy: Promise and ChallengesSci Transl Med 28 March 2012 4:127ps9

VIEW VIDEO

Topol on the Cancer Clinic of the Future

Hello. I’m Dr. Eric Topol, director of the Scripps Translational Science Institute and Editor-in-Chief of Medscape. In this series, The Creative Destruction of Medicine, named for the book I wrote, I am trying to zoom in on critical aspects of how the digital world can create better healthcare.

Cancer care is rapidly changing, if we think about where it was some years ago as it was really beautifully archived in a book by Sid Mukherjee, MD, The Emperor of All Maladies,[1] and to where we can go in the future. Just launched recently, for example, was MD Anderson Cancer Center’s Moon Shots program in cancer care.[2] The Moon Shots program is perhaps, because of genomics, digitizing the genome of the tumor, comparing it with the genome-native germ line. This gives us an opportunity we never had before.

So what is the cancer clinic of the future going to look like, because it’s just starting to get developed today? For example, when we have an individual presenting for a new diagnosis of cancer, we have to move away from fine-needle aspiration and minimal tissue; we need real tissue to be able to process it properly. Not only do we need the formalin-fixed paraffin-embedded (FFPE) specimen, but we also need another type of FF — that is, flash-frozen specimens so that we can then whole-genome sequence this tissue.

Now, when that is done at the primary diagnosis and done within hours and analyzed with the appropriate software algorithms, we could get the driver mutations nailed within 24 hours from the diagnosis. This can set up remarkably precise therapy that can be given to the patient on the basis of that individual’s tumor. There are no 2 different cancers that are the same anywhere. Just like there are no 2 individuals who have the same DNA, that’s the same for a tumor.

One of the issues that we have to confront is that there’s a lot of intratumor heterogeneity. We need multiple samples to sequence from the tumor, and if there’s already a metastatic lesion, we need a sample of that as well. Multiple sequencing, frozen tissue, genome-driven guided therapy — right from the get-go — is what we need. That’s not what we have today, but that’s where we can go in the future of cancer genomic medicine. It’s really an exciting opportunity. It has to be validated.

The cancer drugs that are used today are remarkably expensive, and what’s fascinating is to see — and this is a recurrent theme — is that a drug being used, for example, for renal carcinoma can also be used for leukemia. There was a classic 3-part article on the front page of the New York Times [3] that exemplified some of the stories along those lines.

It’s a story about mutations — a war on mutations, not a war on cancer — and this type of cancer clinic in the future can take us there but there’s going to have to be a whole different look with respect to the way that we take samples of the tumor. We need much more tissue, and to use frozen tissue so that we don’t have to bootstrap the FFPE (that paraffin-embedded specimen) and only get a couple of hundred genes or coding elements, but in fact get a whole genome from the flash-frozen specimen. That’s really important, and we have to move in that direction — get more tissue in order to account for the heterogeneity that we know exists. And we have to do deep sequencing of that frozen tissue in order to get the driver mutations identified, and also be able to anticipate where relapses can occur downstream.

That is precision therapy. This exemplifies the future of cancer genomic medicine, and it will be really interesting to see how that plays out in these cancer clinics of the future.

Thanks so much for joining us for this segment, and stay tuned for more from The Creative Destruction of Medicine series.

References

  1. Mukherjee S. The Emperor of All Maladies: A Biography of Cancer. New York: Scribner; 2010. The 2011 Pulitzer Prize Winners: General Nonfiction. http://www.pulitzer.org/works/2011-General-Nonfiction. Accessed March 5, 2013.
  2. University of Texas MD Anderson Center. Moon Shots program. http://cancermoonshots.org/. Accessed March 5, 2013.
  3. Kolata G. In treatment for leukemia, glimpses of the future. New York Times. July 7, 2012.http://www.nytimes.com/2012/07/08/health/in-gene-sequencing-treatment-for-leukemia-glimpses-of-the-future.html?
  4. pagewanted=all&_r=0. Accessed March 5, 2013.

SOURCE:

http://www.medscape.com/viewarticle/780424?src=emailthis

Charles Swanton Publications

London Research Institute

44 Lincoln’s Inn Fields
London
WC2A 3LY
United Kingdom

Emailcharles.swanton@cancer.org.uk
WebLab website

Primary research papers

The following publications have been supported by Cancer Research UK funding for this researcher.

2010

From genomic landscapes to personalized cancer management-is there a roadmap?
Swanton C;Caldas C
Ann N Y Acad Sci 2010; 1210 ( ):34-44.
PubMed;  DOI: 10.1111/j.1749-6632.2010.05776.x.

Minimising Immunohistochemical False Negative ER Classification Using a Complementary 23 Gene Expression Signature of ER Status
Li QY;Eklund AC;Juul N;Haibe-Kains B;Workman CT;Richardson AL;Szallasi Z;Swanton C
PLoS ONE 2010; (11):e15031.
DOI: 10.1371/journal.pone.0015031.

How Darwinian models inform therapeutic failure initiated by clonal heterogeneity in cancer medicine
Gerlinger M;Swanton C
Br J Cancer 2010; 103 (8):1139-1143.
UKPubMed (open access);  PubMed;  DOI: 10.1038/sj.bjc.6605912.

Anti-cancer drug resistance: Understanding the mechanisms through the use of integrative genomics and functional RNA interference
Tan DSW;Gerlinger M;Teh BT;Swanton C
Eur J Cancer 2010; 46 (12):2166-2177.
PubMed;  DOI: 10.1016/j.ejca.2010.03.019.

A retrospective analysis of clinical outcome of patients with chemo-refractory metastatic breast cancer treated in a single institution phase I unit
Brunetto AT;Sarker D;Papadatos-Pastos D;Fehrmann R;Kaye SB;Johnston S;Allen M;De Bono JS;Swanton C
Br J Cancer 2010; 103 (5):607-612.
PubMed;  DOI: 10.1038/sj.bjc.6605812.

FKBPL Regulates Estrogen Receptor Signaling and Determines Response to Endocrine Therapy
McKeen HD;Byrne C;Jithesh PV;Donley C;Valentine A;Yakkundi A;O’Rourke M;Swanton C;McCarthy HO;Hirst DG;Robson T
Cancer Res 2010; 70 (3):1090-1100.
DOI: 10.1158/0008-5472.CAN-09-2515.

Prognostic and Predictive Biomarkers in Resected Colon Cancer: Current Status and Future Perspectives for Integrating Genomics into Biomarker Discovery
Tejpar S;Bertagnolli M;Bosman F;Lenz HJ;Garraway L;Waldman F;Warren R;Bild A;Collins-Brennan D;Hahn H;Harkin DP;Kennedy R;Ilyas M;Morreau H;Proutski V;Swanton C;Tomlinson I;Delorenzi M;Fiocca R;Van Cutsem E;Roth A
Oncologist 2010; 15 (4):390-404.
DOI: 10.1634/theoncologist.2009-0233.

Assessment of an RNA interference screen-derived mitotic and ceramide pathway metagene as a predictor of response to neoadjuvant paclitaxel for primary triple-negative breast cancer: a retrospective analysis of five clinical trials
Juul N;Szallasi Z;Eklund AC;Li QY;Burrell RA;Gerlinger M;Valero V;Andreopoulou E;Esteva FJ;Symmans WF;Desmedt C;Haibe-Kains B;Sotiriou C;Pusztai L;Swanton C
Lancet Oncol 2010; 11 (4):358-365.
PubMed;  DOI: 10.1016/S1470-2045(10)70018-8.

2009

RNAi-mediated functional analysis of pathways influencing cancer cell drug resistance
Lee AJX;Kolesnick R;Swanton C
Expert Rev Mol Med 2009; 11 ():e15.
PubMed;  DOI: 10.1017/S1462399409001070.

Advances in personalized therapeutics in non-small cell lung cancer: 4q12 amplification, PDGFRA oncogene addiction and sunitinib sensitivity
Swanton C;Burrell RA
Cancer Biol Ther 2009; (21):2051-2053.
PubMed;

Chromosomal instability A composite phenotype that influences sensitivity to chemotherapy
McClelland SE;Burrell RA;Swanton C
Cell Cycle 2009; (20):3262-3266.
PubMed;

Genetic prognostic and predictive markers in colorectal cancer
Walther A;Johnstone E;Swanton C;Midgley R;Tomlinson I;Kerr D
Nat Rev Cancer 2009; (7):489-499.
PubMed;

Chromosomal instability determines taxane response
Swanton C;Nicke B;Schuett M;Eklund AC;Ng C;Li QY;Hardcastle T;Lee A;Roy R;East P;Kschischo M;Endesfelder D;Wylie P;Kim SN;Chen JG;Howell M;Ried T;Habermann JK;Auer G;Brenton JD;Szallasi Z;Downward J
Proc Natl Acad Sci U S A 2009; 106 (21):8671-8676.
UKPubMed (open access);  PubMed;  DOI: 10.1073/pnas.0811835106.

Molecular classification of solid tumours: towards pathway-driven therapeutics
Swanton C;Caldas C
Br J Cancer 2009; 100 (10):1517-1522.
PubMed;

2008

Epothilones and new analogues of the microtubule modulators in taxane-resistant disease
Harrison M;Swanton C
Expert Opin Invest Drugs 2008; 17 (4):523-546.
PubMed;

Targeting Polo-Like Kinase: Learning Too Little Too Late?
Olmos D;Swanton C;de Bono J
J Clin Oncol 2008; 26 (34):5497-5499.
PubMed;

Concordance of exon array and real-time PCR assessment of gene expression following cancer cell cytotoxic drug exposure
Lee AJX;East P;Pepper S;Nicke B;Szallasi Z;Eklund AC;Downward J;Swanton C
Cell Cycle 2008; (24):3947-3948.
PubMed;

Functional genomic analysis of drug sensitivity pathways to guide adjuvant strategies in breast cancer
Swanton C;Szallasi Z;Brenton JD;Downward J
Breast Cancer Res 2008; 10 (5):214.
UKPubMed (open access);  PubMed;  DOI: 10.1186/bcr2159.

Unraveling the complexity of endocrine resistance in breast cancer by functional genomics
Swanton C;Downward J
Cancer Cell 2008; 13 (2):83-85.
PubMed;

146 Publications on PubMed by Polyak’s Lab

Other related articles on this Open Access Online Scientific Journal include the following:

Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

Stephen J. Williams, Ph.D. 4/10/2013

https://pharmaceuticalintelligence.com/2013/04/10/issues-in-personalized-medicine-in-cancer-intratumor-heterogeneity-and-branched-evolution-revealed-by-multiregion-sequencing/

Pfizer’s Kidney Cancer Drug Sutent Effectively caused REMISSION to Adult Acute Lymphoblastic Leukemia (ALL)

Aviva Lev-Ari, PhD, RN, 7/10/2012

https://pharmaceuticalintelligence.com/2012/07/10/pfizers-kidney-cancer-drug-sutent-effectively-caused-remission-to-adult-acute-lymphoblastic-leukemia-all/

On Tumor and mutations

https://pharmaceuticalintelligence.com/?s=tumor+mutations

On ‘genomics mutations’

https://pharmaceuticalintelligence.com/?s=genomics+mutations

On ‘cancer sequencing’

https://pharmaceuticalintelligence.com/?s=cancer+sequencing

 On Metastasis
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