Periodic Reporting for period 2 - COLOSSUS (Advancing a Precision Medicine Paradigm in metastatic Colorectal Cancer: Systems based patient stratification solutions)
Reporting period: 2019-07-01 to 2020-12-31
Colorectal cancer (CRC) is the third most common cancer in Europe with 530,611 new 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.
In the first three years of the project, COLOSSUS has made good progress towards the achievement of our key goals and objectives.
Much of our work in the initial phase of the project was focused on securing access to retrospective samples from biobanks and initiating the COLOSSUS translational trial, which is being conducted across Spain, Germany and Ireland.
During Reporting Period 2, we have finalised our retrospective Stage 2/3 MSS RAS mt CRC samples cohort and completed the related ‘omics analysis. We have also commenced multi-omic analyses of our mCRC (Stage 4) cohort. To date, copy number alteration (CNA), transcriptomic, metabolomic and proteomic profiling of the COLOSSUS retrospective cohort has been completed and reported, as well as the CNA profiling of PDX models.
Novel clustering algorithms have been applied to the data generated from our ‘omics analysis and new integrated molecular and functional MSS RAS mt ‘COLOSSUS’ subtypes have been identified. This is a key milestone for the project which allows downstream analysis and work streams to progress. This includes promising early work on network & pathway modelling of multi‘omic MSS RAS mt CRC datasets, working towards the identification of new therapeutic targets across COLOSSUS subtypes.
The data we have generated is stored in the COLOSSUS data storage and sharing platform at ICR and a comprehensive Data Management Plan is in place. Significant effort has also been focused on ensuring all ethics requirements related to the project have been addressed.
Preparatory work has also been undertaken in the period towards the development of clinical diagnostic assay prototypes for stratification of MSS RAS mt patients based on COLOSSUS subtypes. Moreover, groundwork has been laid for work on the pre-clinical validation of novel therapeutic strategies.
COLOSSUS has developed a proactive communication and dissemination programme. This is maintained through the project website (https://www.colossusproject.eu/) and social media accounts (https://twitter.com/COLOSSUSEU https://www.facebook.com/COLOSSUSEU/ and ResearchGate: link). Over the course of the project we have issued press releases, promotional materials and peer reviewed publications (16 papers at the time of writing: https://www.colossusproject.eu/project-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.
Much of our work in the initial phase of the project was focused on securing access to retrospective samples from biobanks and initiating the COLOSSUS translational trial, which is being conducted across Spain, Germany and Ireland.
During Reporting Period 2, we have finalised our retrospective Stage 2/3 MSS RAS mt CRC samples cohort and completed the related ‘omics analysis. We have also commenced multi-omic analyses of our mCRC (Stage 4) cohort. To date, copy number alteration (CNA), transcriptomic, metabolomic and proteomic profiling of the COLOSSUS retrospective cohort has been completed and reported, as well as the CNA profiling of PDX models.
Novel clustering algorithms have been applied to the data generated from our ‘omics analysis and new integrated molecular and functional MSS RAS mt ‘COLOSSUS’ subtypes have been identified. This is a key milestone for the project which allows downstream analysis and work streams to progress. This includes promising early work on network & pathway modelling of multi‘omic MSS RAS mt CRC datasets, working towards the identification of new therapeutic targets across COLOSSUS subtypes.
The data we have generated is stored in the COLOSSUS data storage and sharing platform at ICR and a comprehensive Data Management Plan is in place. Significant effort has also been focused on ensuring all ethics requirements related to the project have been addressed.
Preparatory work has also been undertaken in the period towards the development of clinical diagnostic assay prototypes for stratification of MSS RAS mt patients based on COLOSSUS subtypes. Moreover, groundwork has been laid for work on the pre-clinical validation of novel therapeutic strategies.
COLOSSUS has developed a proactive communication and dissemination programme. This is maintained through the project website (https://www.colossusproject.eu/) and social media accounts (https://twitter.com/COLOSSUSEU https://www.facebook.com/COLOSSUSEU/ and ResearchGate: link). Over the course of the project we have issued press releases, promotional materials and peer reviewed publications (16 papers at the time of writing: https://www.colossusproject.eu/project-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 mt mCRC 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, 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.
During the first three years of the project COLOSSUS has been working towards the identification of novel COLOSSUS subtypes for MSS RAS mt CRC, which has now been achieved. This is a major milestone for the project, and now allows downstream analsyes and workstreams to progress.
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 and more effective 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 will yield energy savings and environmental benefits.
(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.
During the first three years of the project COLOSSUS has been working towards the identification of novel COLOSSUS subtypes for MSS RAS mt CRC, which has now been achieved. This is a major milestone for the project, and now allows downstream analsyes and workstreams to progress.
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 and more effective 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 will yield energy savings and environmental benefits.