Periodic Reporting for period 3 - COLOSSUS (Advancing a Precision Medicine Paradigm in metastatic Colorectal Cancer: Systems based patient stratification solutions) Reporting period: 2021-01-01 to 2022-06-30 Summary of the context and overall objectives of the project 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 omics and longitudinal imaging 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 are then being 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). COLOSSUS partners are developing 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. Patient associations are included, and the programme considers regulatory aspects and commercialisation opportunities, in particular for participating SMEs. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far COLOSSUS has made good progress so far towards the achievement of our key goals and objectives.Key achievements by the end of June 2022 include the following:• We have finalised our retrospective cohort of samples from 184 Stage 2/3 MSS RAS mt mCRC patients and our mCRC cohort of samples (Stage 4) from 121 patients (COLOSSUS trial and trial proxy cohorts).• The COLOSSUS translational trial has been completed, with the last patient off study in April 2022. • Multi-omic profiling of MSS RAS mt CRC COLOSSUS cohorts is substantially complete and radiomics analyses are ongoing. • By integrating multi-‘omics and immune profiling data, we have identified new ‘MSS RAS mt CRC (designated ‘COLOSSUS’) subtypes and have validated COLOSSUS subtypes in two cohorts. In RP3 we worked on reduced gene expression profiles and further studied prognostic associations and pathways. COLOSSUS subtype-specific CpG regions and pathways enriched for mutations in each COLOSSUS subtype have been identified. Master regulator networks across COLOSSUS subtypes have been explored, and drugs targeting master regulators have been proposed. Pathways enriched in each subtype have been identified, and the activity of key pathways has been modelled.• We have advanced the development of clinical diagnostic assay prototypes for stratification of MSS RAS mt patients based on novel Ras mutant mCRC subtypes and our model for the economic assessment of treatment based on diagnostic tests.• We have generated initial promising results from pharmacological experiments in COLOSSUS-subtyped organoids, exploring inhibitors against targets based primarily on the results of systems medicine network modelling.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. 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). Over the course of the project we have issued press releases, promotional materials and peer reviewed publications (26 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 at: https://www.youtube.com/watch?v=-Zxym7__7yA&feature=youtu.be. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) 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.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. Ultimately COLOSSUS aims to provide new and more effective ways to classify patients with MSS RAS mt mCRC, to develop better treatments for them and to deliver a personalised medicine approach for patients with MSS RAS mt mCRC that is currently not available. We believe our work will benefit patients and their families, clinicians and health care systems and deliver wider economic benefits. Our work during RP3 brings the achievement of these aims ever closer to fruition. Related documents Colossus_small.jpg 2022-08-24_202245.jpg 2022-08-24_201720.jpg
