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Advancing a Precision Medicine Paradigm in metastatic Colorectal Cancer: Systems based patient stratification solutions

Periodic Reporting for period 1 - COLOSSUS (Advancing a Precision Medicine Paradigm in metastatic Colorectal Cancer: Systems based patient stratification solutions)

Reporting period: 2018-01-01 to 2019-06-30

Colorectal cancer (CRC) is the third most common cancer in Europe with 530,611 cases and 260,000 related deaths in 2018. Of total CRC cases, it is estimated that approximately 50-55 % harbour RAS mutations. Current treatment for RAS mutant (mt) metastatic(m) CRC is primarily based on 5-fluoruracil based chemotherapy +/- bevacizumab. However, there are currently limited treatment options once cancers have become resistant. Moreover, while therapy optimization strategies in RAS wild-type CRC patients are feasible, targeted treatment of microsatellite stable (MSS) RAS mt disease is difficult and has not evolved significantly in recent years. COLOSSUS is working 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. The consortium is integrating multidimensional and longitudinal omics data to identify new MSS RAS mt specific subtypes with unique signalling dependences. We are further harnessing the power of systems biomedicine, network analysis and computational modelling to identify new actionable pathways, biomarkers and targets across subtypes. These targets will ultimately be interrogated in patient derived xenograft studies. Newly described MSS RAS mt classifiers will further be validated as novel patient stratification tools within the COLOSSUS trial (NCT03699111). SME partners are developing clinically relevant and commercially viable assays for outcome prediction and stratification of MSS RAS mt patients based on novel classifiers. The impact of assays on CRC associated healthcare costs will further be assessed. Patient associations are included, and the programme considers regulatory aspects and commercialisation opportunities, in particular for participating SMEs. mCRC is a complex disease having high prevalence and high economic impact both within a European and global context.
In the first 18 months since the project began (Jan 2018), COLOSSUS has made significant progress in the implementation of core management (PT, RCSI) and technical activities which are key to the future success of the programme.

We established our management infrastructure, tools and processes at the start of the Project and project management has proceeded effectively throughout the period. Co-ordination tools and activities included meetings, TCs, file-sharing, mailing lists, project calendar, quality assurance (QA) process, internal reporting, budget tracking, risk reviews and gender equality awareness.

In the scientific WPs, retrospectively collected tumour samples from MSS RAS mt patients have been identified by contributing biobanks (VHIO, INSERM/CHU-Toulouse, RCSI) with all samples having been reviewed by the relevant pathologist(s). Samples have subsequently been processed at the central COLOSSUS nucleotide extraction laboratory at RCSI and extracted oligonucleotides/ tissue delivered to consortium partners for downstream analyses as required. Thus, multi-omic profiling (eg Next Generation Sequencing, metabolomics, multiplexed immunohistochemistry) of retrospective samples has commenced at VIB, RCSI and INSERM.

The COLOSSUS data storage and sharing platform has been established at ICR and a comprehensive Data Management Plan is in place.

Importantly, the COLOSSUS international translational trial (NCT01822444) coordinated by CTI and with participation from UHEI and VHIO has been opened in Ireland, Germany and Spain.

Much preparatory work has also been commenced by several SMEs (HDX, EPI, OPTI) and academic partners (UCD, UNITO, RCSI) tasked with activities due to commence after June 2019. The consortium has dealt efficiently with unavoidable delays encountered due to new GDPR legislation and all appropriate ethics processes are in place.

Finally, COLOSSUS has developed a proactive communication and dissemination programme. During the period we established the project website (https://www.colossusproject.eu/) and social media accounts (https://twitter.com/COLOSSUSEU https://www.facebook.com/COLOSSUSEU/ and ResearchGate). We issued press releases, promotional materials and peer reviewed publications and presented on COLOSSUS at numerous key conferences. Our COLOSSUS explainer video can be viewed here: https://www.youtube.com/watch?v=-Zxym7__7yA&feature=youtu.be.
There are currently limited treatment options once RAS mutant (mt) metastatic CRC patients have become resistant. Thus, there exists an urgent clinical need for a more personalised treatment paradigm in this setting. The fundamental objective of COLOSSUS is to provide new and more effective stratification tools and therapeutic interventions, specifically tailored to poor prognosis, difficult to treat, microsatellite stable (MSS) RAS mt mCRC patients. The COLOSSUS consortium is delivering impact and progress beyond the state of the art across six key areas:

(1) Establishing new subtypes for MSS RAS mt CRC patient stratification & treatment.
(2) Implementing an integrative Systems Modelling framework for the discovery of new methods for MSS RAS mt CRC patient stratification and treatment.
(3) Establishing clinically feasible computational tools to predict MSS RAS mt patient response.
(4) Developing new clinically applicable diagnostic test prototypes to stratify MSS RAS mt CRC patients.
(5) Identifying and testing new combinatorial treatment options for MSS RAS mt CRC patients.
(6) Developing new algorithms to identify pathway-based biomarkers for stratifying CRC subtypes.

While the programme is yet at an early stage, during this first 18 month period COLOSSUS has initiated key management and technical activities towards the realisation of these impacts. In particular establishment of the COLOSUS biobank and data exchange portal and opening of the international COLOSSUS translational trial (NCT01822444) have been important milestones in the programme.

Critically, as c.30% of all human cancers possess activating RAS mutations data emerging from COLOSSUS on new biomarkers, stratification models, novel drug combinations and therapeutic strategies in the RAS mt setting may have significant additional impact within the broader oncology space. The benefits of COLOSSUS will primarily be experienced by patients, clinicians and healthcare systems. However, there are ‘knock-on’ impacts for society as a whole and for the environment: (1) Patients will spend less time recovering from therapy side-effects and will receive more effective treatment in a timely manner. This will enable them to remain in (or return to) the workforce, where appropriate; (2) The burden of informal patient care for carers and social networks of cancer patients will decrease with better treatments, improving their quality of life and enabling them to contribute more effectively to the workforce and to society as a whole; (3) Significant savings in healthcare realized through better mCRC treatments will mean more funding is available for other social assets; (4) Reduced travel for treatment, reduced hospital time and avoidance of ineffective therapies means savings in terms of energy and environmental pollutants.
COLOSSUS Partners - Logos
Screenshot of COLOSSUS Project homepage - https://www.colossusproject.eu
COLOSSUS Team at Plenary Meeting, Barcelona December 2018