Researchers2018-11-02T15:55:22+00:00

Overview of the COLOSSUS Project

COLOSSUS aims to provide new and more effective stratification tools and therapeutic interventions, specifically tailored to MSS RAS mt mCRC patients. mCRC is a heterogenous disease with high prevalence and significant economic impact both within a European and global context. COLOSSUS aims to deliver novel concepts for disease-mechanism based patient stratification in MSS RAS mt mCRC to address the need for stratified or personalised therapeutic interventions in this setting.

To achieve its aims the consortium will integrate multidimensional and longitudinal ‘omics data to help identify new MSS RAS mt specific subtypes with unique signalling dependences. We will harness the power of systems biomedicine, network analysis and computational modelling to identify new actionable pathways, biomarkers and targets across subtypes and to predict patient outcomes. These targets will be interrogated in state of the art pre-clinical patient derived xenograft studies. Newly described MSS RAS mt classifiers will be validated as novel patient stratification tools within the COLOSSUS trial. SME partners aim to develop clinically relevant and commercially viable assays for stratification of MSS RAS mt patients based on novel classifiers. The impact of assays on CRC associated healthcare costs will further be assessed.

We will disseminate our results and reach clinicians, researchers and related projects, industry and SMEs, government and policy-makers, the media, the general public, patients and patient representative groups. We will also consider regulatory aspects and commercialisation opportunities, in particular for participating SMEs.

Our Research Plan

Our work in COLOSSUS is broken into the following different work packages:

  • WP1 Project Management

  • WP2 COLOSSUS Biorepository & Histopathology Analyses: retrospective tumour samples and prospective samples (from the COLOSSUS clinical trial) from stage 2/3 MSS RAS mt CRC patients and related data will be collected, reviewed, assessed, coded and collated at the COLOSSUS bio-repository.

  • WP3 COLOSSUS Translational Trial: A multicentre trial for advanced MSS RAS mt mCRC patients receiving SOC chemotherapy +/- bvz will be conducted in Spain, Germany and Ireland, respectively. The primary objective will be to identify a new patient stratification tool in MSS RAS mt mCRC using a novel integrative systems biomedicine multi-‘omic discovery framework. The secondary objective will be to clinically validate newly discovered COLOSSUS and existing classifiers as new treatment stratification tools for MSS RAS mt patients receiving SOC chemotherapy +/- bevacizumab.

  • WP4 Multi-‘omic profiling of MSS RAS mt retrospective and prospective cohorts: Multi-omic profiling (transcriptomics, genomics, metabolomics, epigenomics, proteomics) will be performed on retrospectively and prospectively collected Stage IV FF and FFPE MSS RAS mt primary tumours and on longitudinally collected blood samples and metastatic biopsies.

  • WP5 Identification and phenotypic analysis of new MSS CRC RAS mt patient stratification subtypes: A bioinformatics database will be established for emerging data (WP3, WP4), together with a data management plan. All retrospectively and prospectively collected MSS RAS mt tumours will be sub-typed using existing CMS gene expression classifiers to characterize MSS RAS mt cohorts. Novel clustering algorithms will also be applied to identify new integrated molecular and functional MSS RAS mt subtypes associated with clinic-pathological features and patient survival. We will also interrogate transcriptomic data sets to specifically analyse the immune, fibroblastic and angiogenic microenvironment.

  • WP6 Network & Pathway Modelling of multi-‘omic MSS RAS mt CRC datasets: Identification of new therapeutic targets across COLOSSUS subtypes: Once tumours are allocated to subtypes, a novel systems medicine framework will be implemented to integrate multi-omics data sets and perform network modelling towards the discovery of new biomarkers and actionable therapeutic targets, which we anticipate will differ dependent on subtypes. We will adopt a multi-dimensional approach which aims to yield a highly integrated computational model for prediction of clinical outcome.

  • WP7 Clinical diagnostic assay prototypes for clinical stratification of MSS RAS mt patients based on newly derived COLOSSUS subtypes: Newly described COLOSSUS MSS RAS mt CRC subtype classifiers will be translated into tissue based targeted Next-Generation Sequencing (NGS) assays to enable fast and efficient patient stratification. Bisulfite multiplex PCRs measured by NGS will also be established as test prototypes to assess DNA-methylation biomarkers for stratification of MSS RAS mt CRC cohorts with potential for clinical application as liquid biopsies. Economic analysis of the COLOSSUS MSS RAS mt CRC subtype classifiers will be carried out to determine the cost effectiveness of the diagnostic technologies.

  • WP8 Pre-clinical interrogation of novel combinatorial treatment strategies for MSS RAS mt mCRC subtypes using PDX and HuPDX population trials: New insights into drug response will be generated by the project. In WP8 novel combinational treatment strategies for MSS RAS mt mCRC subtypes will be tested in a pre-clinical setting e.g. in (Hu)PDX models.

  • WP9 Communication, Dissemination, Exploitation and Training.

  • WP10 Ethics

Illustration of the COLOSSUS Work plan

Illustration of the COLOSSUS Work plan

Innovation

COLOSSUS aims to deliver and employ numerous different innovations. These will include:

  • Identification of new subtypes for MSS RAS mt CRC patient stratification & treatment.

  • Development and application of an integrative systems modelling framework for the discovery of new methods for MSS RAS mt CRC patient stratification and treatment.

  • Delivery of clinically feasible computational tools to predict MSS RAS mt patient response.

  • Production of new clinically applicable MDx test prototypes to stratify MSS RAS mt CRC patients.

  • Identification of new combinatorial treatment options for MSS RAS mt CRC patients.

  • Development of new algorithms to identify pathway-based biomarkers for stratifying CRC subtypes.

Project Publications and Related Projects

You can access COLOSSUS project publications (as they become available here). You can access details of related projects here.

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