Personalized medicine approaches for colon cancer driven by genomics and systems biology: OncoTrack

The post‐genomic era promises to pave the way to a personalized understanding of disease processes, with technological and analytical advances helping to solve some of the world's health challenges. Despite extraordinary progress in our understanding of cancer pathogenesis, the disease remains one of the world's major medical problems. New therapies and diagnostic procedures to guide their clinical application are urgently required. OncoTrack, a consortium between industry and academia, supported by the Innovative Medicines Initiative, signifies a new era in personalized medicine, which synthesizes current technological advances in omics techniques, systems biology approaches, and mathematical modeling. A truly personalized molecular imprint of the tumor micro‐environment and subsequent diagnostic and therapeutic insight is gained, with the ultimate goal of matching the “right” patient to the “right” drug and identifying predictive biomarkers for clinical application. This comprehensive mapping of the colon cancer molecular landscape in tandem with crucial, clinical functional annotation for systems biology analysis provides unprecedented insight and predictive power for colon cancer management. Overall, we show that major biotechnological developments in tandem with changes in clinical thinking have laid the foundations for the OncoTrack approach and the future clinical application of a truly personalized approach to colon cancer theranostics.

[1]  A. Y. Lu,et al.  Pharmacogenomics and Individualized Medicine , 2012 .

[2]  M. Junttila,et al.  Influence of tumour micro-environment heterogeneity on therapeutic response , 2013, Nature.

[3]  K. Pantel,et al.  Circulating tumor cells and circulating tumor DNA. , 2012, Annual review of medicine.

[4]  M. Stratton,et al.  COSMIC 2005 , 2006, British Journal of Cancer.

[5]  Michael Scholz,et al.  Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS wild-type metastatic colorectal cancer: German AIO study KRK-0306 (FIRE-3). , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[7]  U. Landegren,et al.  Direct observation of individual endogenous protein complexes in situ by proximity ligation , 2006, Nature Methods.

[8]  Trisilowati,et al.  In Silico Experimental Modeling of Cancer Treatment , 2012, ISRN oncology.

[9]  M Heath-Chiozzi,et al.  Clinical application of pharmacogenetics. , 2001, Trends in molecular medicine.

[10]  S. Gabriel,et al.  Advances in understanding cancer genomes through second-generation sequencing , 2010, Nature Reviews Genetics.

[11]  Mehmet Toner,et al.  Detection of mutations in EGFR in circulating lung-cancer cells. , 2008, The New England journal of medicine.

[12]  Rui Chen,et al.  Promise of personalized omics to precision medicine , 2013, Wiley interdisciplinary reviews. Systems biology and medicine.

[13]  Alice Bidwell Wesenberg.  Cosmic , 1929 .

[14]  Steven J. M. Jones,et al.  Comprehensive molecular characterization of human colon and rectal cancer , 2012, Nature.

[15]  Takayuki Sugiyama,et al.  Critical roles of DMP1 in human epidermal growth factor receptor 2/neu-Arf-p53 signaling and breast cancer development. , 2010, Cancer research.

[16]  D. Mccormick.  Sequence the Human Genome , 1986, Bio/Technology.

[17]  L. Hood,et al.  A personal view on systems medicine and the emergence of proactive P4 medicine: predictive, preventive, personalized and participatory. , 2012, New biotechnology.

[18]  G. Parmigiani,et al.  The Consensus Coding Sequences of Human Breast and Colorectal Cancers , 2006, Science.

[19]  Richard Sullivan,et al.  Economic burden of cancer across the European Union: a population-based cost analysis. , 2013, The Lancet. Oncology.

[20]  C. Glackin,et al.  A reconstructed metastasis model to recapitulate the metastatic spread in vitro , 2014, Biotechnology journal.

[21]  Corbin E. Meacham,et al.  Tumour heterogeneity and cancer cell plasticity , 2013, Nature.

[22]  Tom Royce,et al.  A comprehensive catalogue of somatic mutations from a human cancer genome , 2010, Nature.

[23]  Sheila M. Reynolds,et al.  Integrated analyses identify a master microRNA regulatory network for the mesenchymal subtype in serous ovarian cancer. , 2013, Cancer cell.

[24]  G. Parmigiani,et al.  Integrated analysis of homozygous deletions, focal amplifications, and sequence alterations in breast and colorectal cancers , 2008, Proceedings of the National Academy of Sciences.

[25]  A. Lièvre,et al.  KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. , 2006, Cancer research.

[26]  D. Busam,et al.  An Integrated Genomic Analysis of Human Glioblastoma Multiforme , 2008, Science.

[27]  Vittorio Cristini,et al.  Multiscale cancer modeling. , 2010, Annual review of biomedical engineering.

[28]  E. Birney,et al.  Patterns of somatic mutation in human cancer genomes , 2007, Nature.

[29]  V. Anne Smith,et al.  Erratum to: Cancer Systems Biology , 2010 .

[30]  E. Birney,et al.  A small cell lung cancer genome reports complex tobacco exposure signatures , 2009, Nature.

[31]  Frank Morgner,et al.  A quantum-dot-based molecular ruler for multiplexed optical analysis. , 2010, Angewandte Chemie.

[32]  Laurent Gil,et al.  Ensembl 2013 , 2012, Nucleic Acids Res..

[33]  J. Bonfield,et al.  Finishing the euchromatic sequence of the human genome , 2004, Nature.

[34]  G. Parmigiani,et al.  Design and analysis issues in genome-wide somatic mutation studies of cancer. , 2009, Genomics.

[35]  Ulrich Keilholz,et al.  Eradication of EGFR-positive circulating tumor cells and objective tumor response with lapatinib and capecitabine , 2010, Cancer biology & therapy.

[36]  Carolina Wählby,et al.  In situ sequencing for RNA analysis in preserved tissue and cells , 2013, Nature Methods.

[37]  Zigang Dong,et al.  Post-translational modification of p53 in tumorigenesis , 2004, Nature Reviews Cancer.

[38]  Eli Upfal,et al.  De Novo Discovery of Mutated Driver Pathways in Cancer , 2011, RECOMB.

[39]  David J Harrison,et al.  Cancer systems biology. , 2016, Methods in molecular biology.

[40]  Ilya Shmulevich,et al.  Integrated analyses identify a master microRNA regulatory network for the mesenchymal subtype in serous ovarian cancer. , 2013, Cancer cell.

[41]  Brian Ingalls,et al.  Modeling of cell culture damage and recovery leads to increased antibody and biomass productivity in CHO cell cultures , 2014, Biotechnology journal.

[42]  Melanie I. Stefan,et al.  BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models , 2010, BMC Systems Biology.

[43]  K. Kinzler,et al.  Cancer Genome Landscapes , 2013, Science.

[44]  Hugh Laverty,et al.  Editorial: The Innovative Medicines Initiative – collaborations are key to innovating R&D processes , 2014, Biotechnology journal.

[45]  The Cancer Genome Atlas Research Network,et al.  Comprehensive molecular characterization of urothelial bladder carcinoma , 2014, Nature.

[46]  P. A. Futreal,et al.  Emerging patterns of somatic mutations in cancer , 2013, Nature Reviews Genetics.

[47]  J. Chen,et al.  Post-translational modifications and the Warburg effect , 2014, Oncogene.

[48]  Susumu Goto,et al.  Data, information, knowledge and principle: back to metabolism in KEGG , 2013, Nucleic Acids Res..

[49]  Matthew J. Betts,et al.  Dissecting the genomic complexity underlying medulloblastoma , 2012, Nature.

[50]  U Klingmüller,et al.  Predictive mathematical models of cancer signalling pathways , 2012, Journal of internal medicine.

[51]  E. Birney,et al.  Patterns of somatic mutation in human cancer genomes , 2007, Nature.

[52]  S. Gabriel,et al.  Discovery and saturation analysis of cancer genes across 21 tumor types , 2014, Nature.

[53]  R. Wilson,et al.  Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. , 2010, Cancer cell.

[54]  R. Labianca,et al.  Primary colon cancer: ESMO Clinical Practice Guidelines for diagnosis, adjuvant treatment and follow-up. , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[55]  Hiroaki Kitano,et al.  The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models , 2003, Bioinform..

[56]  Pamela K. Kreeger,et al.  Cancer systems biology: a network modeling perspective , 2009, Carcinogenesis.

[57]  V. Beneš,et al.  Integrative genomic analyses reveal an androgen-driven somatic alteration landscape in early-onset prostate cancer. , 2013, Cancer cell.

[58]  Hans-Gerd Löhmannsröben,et al.  Six-color time-resolved Förster resonance energy transfer for ultrasensitive multiplexed biosensing. , 2013, Journal of the American Chemical Society.

[59]  M. Stratton,et al.  Deciphering Signatures of Mutational Processes Operative in Human Cancer , 2013, Cell reports.

[60]  S. Nishizuka,et al.  Reverse-phase protein lysate microarrays for cell signaling analysis , 2008, Nature Protocols.

[61]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[62]  Rui Chen,et al.  Systems biology: personalized medicine for the future? , 2012, Current opinion in pharmacology.

[63]  David T. W. Jones,et al.  Signatures of mutational processes in human cancer , 2013, Nature.

[64]  Gary D Bader,et al.  International network of cancer genome projects , 2010, Nature.

[65]  R Dulbecco,et al.  A turning point in cancer research: sequencing the human genome. , 1986, Science.

[66]  N. McGranahan,et al.  The causes and consequences of genetic heterogeneity in cancer evolution , 2013, Nature.

[67]  Andriani Daskalaki,et al.  High-Throughput miRNA and mRNA Sequencing of Paired Colorectal Normal, Tumor and Metastasis Tissues and Bioinformatic Modeling of miRNA-1 Therapeutic Applications , 2013, PloS one.

[68]  Andriani Daskalaki,et al.  Prediction in the face of uncertainty: a Monte Carlo-based approach for systems biology of cancer treatment. , 2012, Mutation research.

[69]  Bernhard O. Palsson,et al.  Identification of Potential Pathway Mediation Targets in Toll-like Receptor Signaling , 2009, PLoS Comput. Biol..

[70]  Susan Richman,et al.  Panitumumab and irinotecan versus irinotecan alone for patients with KRAS wild-type, fluorouracil-resistant advanced colorectal cancer (PICCOLO): a prospectively stratified randomised trial , 2013, The Lancet. Oncology.

[71]  B. Timmermann,et al.  The power of NGS technologies to delineate the genome organization in cancer: from mutations to structural variations and epigenetic alterations , 2011, Cancer and Metastasis Reviews.

[72]  G. Dranoff,et al.  Combining immunotherapy and targeted therapies in cancer treatment , 2012, Nature Reviews Cancer.

[73]  Edda Klipp,et al.  Systems Biology , 1994 .

[74]  Steven J. M. Jones,et al.  Comprehensive molecular portraits of human breast tumours , 2013 .

[75]  James A. Eddy,et al.  In silico models of cancer , 2010, Wiley interdisciplinary reviews. Systems biology and medicine.

[76]  S. O'keefe,et al.  Nutrition and colonic health: the critical role of the microbiota , 2008, Current opinion in gastroenterology.

[77]  R. Labianca,et al.  Molecular markers and biological targeted therapies in metastatic colorectal cancer: expert opinion and recommendations derived from the 11th ESMO/World Congress on Gastrointestinal Cancer, Barcelona, 2009. , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[78]  A. Sparks,et al.  The Genomic Landscapes of Human Breast and Colorectal Cancers , 2007, Science.

[79]  A. Y. Lu,et al.  Pharmacogenetics, Pharmacogenomics, and Individualized Medicine , 2011, Pharmacological Reviews.

[80]  A. Feinberg,et al.  Genome-wide methylation analysis of human colon cancer reveals similar hypo- and hypermethylation at conserved tissue-specific CpG island shores , 2008, Nature Genetics.

[81]  Heiko Enderling,et al.  Simulating Cancer: Computational Models in Oncology , 2013, Front. Oncol..

[82]  Niko Hildebrandt,et al.  Nanobodies and nanocrystals: highly sensitive quantum dot-based homogeneous FRET immunoassay for serum-based EGFR detection. , 2014, Small.

[83]  Jeremy Purvis,et al.  Role of Network Branching in Eliciting Differential Short‐Term Signaling Responses in the Hypersensitive Epidermal Growth Factor Receptor Mutants Implicated in Lung Cancer , 2008, Biotechnology progress.

[84]  J. Bonfield,et al.  Finishing the euchromatic sequence of the human genome , 2004, Nature.

[85]  H. Johnsen,et al.  Cancer stem cell definitions and terminology: the devil is in the details , 2012, Nature Reviews Cancer.

[86]  H. Lenz,et al.  Integrating biomarkers into clinical decision making for colorectal cancer. , 2010, Clinical colorectal cancer.

[87]  Brian H. Dunford-Shore,et al.  Somatic mutations affect key pathways in lung adenocarcinoma , 2008, Nature.

[88]  Anatoliy Markiv,et al.  Beyond the genome and proteome: targeting protein modifications in cancer. , 2012, Current opinion in pharmacology.

[89]  Yong Bae Kim,et al.  P63 and EGFR as prognostic predictors in stage IIB radiation-treated cervical squamous cell carcinoma. , 2003, Gynecologic oncology.

[90]  Jeremy Purvis,et al.  Molecular systems biology of ErbB1 signaling: bridging the gap through multiscale modeling and high-performance computing. , 2008, Molecular bioSystems.

[91]  Michael Scholz,et al.  Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS-wildtype metastatic colorectal cancer: German AIO study KRK-0306 (FIRE-3). , 2013 .

[92]  H. Lenz,et al.  Molecular Markers in the Treatment of Metastatic Colorectal Cancer , 2010, Cancer journal.

[93]  Scott D. Patterson,et al.  Analysis of KRAS/NRAS and BRAF mutations in the phase III PRIME study of panitumumab (pmab) plus FOLFOX versus FOLFOX as first-line treatment (tx) for metastatic colorectal cancer (mCRC). , 2013 .

[94]  H. Kitano,et al.  A comprehensive pathway map of epidermal growth factor receptor signaling , 2005, Molecular systems biology.

[95]  Axel Kowald,et al.  Systems Biology - a Textbook , 2016 .

[96]  Aleix Prat Aparicio.  Comprehensive molecular portraits of human breast tumours , 2012 .

[97]  M. Pelizzola,et al.  The DNA methylome , 2011, FEBS letters.

[98]  Hans-Gerd Löhmannsröben,et al.  Quantum dot biosensors for ultrasensitive multiplexed diagnostics. , 2010, Angewandte Chemie.

[99]  Roland Eils,et al.  Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma , 2013, Nature Genetics.

[100]  Andrew B Goryachev,et al.  Systems biology: design principles of whole biological systems. Preface. , 2012, Advances in experimental medicine and biology.

[101]  H. Lehrach,et al.  Genomics and epigenomics of colorectal cancer , 2013, Wiley interdisciplinary reviews. Systems biology and medicine.

[102]  U. Landegren,et al.  Protein detection using proximity-dependent DNA ligation assays , 2002, Nature Biotechnology.

[103]  Marco Mignardi,et al.  In situ detection of individual mRNA molecules and protein complexes or post-translational modifications using padlock probes combined with the in situ proximity ligation assay , 2013, Nature Protocols.