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

Periodic Reporting for period 4 - COLOSSUS (Advancing a Precision Medicine Paradigm in metastatic Colorectal Cancer: Systems based patient stratification solutions)

Reporting period: 2022-07-01 to 2023-06-30

It is estimated that colorectal cancer (CRC) accounted for 12.7% of all new cancer diagnoses in the EU in 2020 and 12.4% of all deaths due to cancer. Of total CRC cases, it is believed that approximately 40 % 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.

From the outset the COLOSSUS project has aimed 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 COLOSSUS consortium has generated and integrated multidimensional omics data derived from patient samples to identify new MSS RAS mt specific subtypes. The project has harnessed the power of systems biomedicine, network analysis and computational modelling to identify new actionable pathways, biomarkers and targets. These targets were then interrogated in patient derived xenograft studies. Newly described MSS RAS mt classifiers were also further tested for the stratification of patients within the COLOSSUS translational trial (NCT03699111).
The COLOSSUS project is now complete. Key achievements delivered during COLOSSUS include the following:

• We developed a biorepository of CRC patient samples including (1) the COLOSSUS retrospective cohort from 184 Stage 2/3 MSS RAS mt mCRC patients and (2) the COLOSSUS mCRC cohort (Stage 4) from 121 patients (COLOSSUS trial and trial proxy cohorts).
• We delivered the COLOSSUS translational trial across 3 countries which generated samples for the mCRC cohort, with the last patient off study in April 2022.
• We carried out multi-omics and immune profiling of the COLOSSUS cohorts and radiomics analyses of trial proxy samples.
• By integrating multi-‘omics profiling data using novel clustering algorithms, we identified new ‘MSS RAS mt CRC subtypes and validated these COLOSSUS subtypes in two cohorts.
• We undertook systems network and pathway modelling and derived therapeutic hypotheses for the treatment of mCRC based on pathway activities reconstructed in silico.
• The therapeutic hypotheses developed were tested in representative examples of COLOSSUS-subtyped PDX-derived organoids and co-cultures of organoids and immune cells. The most promising therapies were then finally tested in vivo in matched PDXs and in HuPDX models.
• The pre-clinical validations of novel therapeutic strategies carried out in the project have shown promising potential for broad application across MSS RAS mutant CRC cohorts (although further work is needed to explore and validate results).
• We have developed a computational device/framework for potential application in the modelling of individual MSS RAS mt patients.
• We completed clinical radiomics analyses of the COLOSSUS trial proxy cohorts, developing novel, non-invasive imaging biomarkers.
• We have produced a complex cost-effectiveness model to assess subtype-specific treatment in mCRC.
• We have developed new opportunities for commercial exploitation for COLOSSUS partners GEX (in the field of pathway- and network-based predictions) and Veracyte (new biopharma Atlas).

The data we have generated is stored in the COLOSSUS data storage and sharing platform at ICR and a comprehensive Data Management Plan has been put 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 has been anchored by the project website (https://www.colossusproject.eu/) and social media accounts (https://twitter.com/COLOSSUSEU https://www.facebook.com/COLOSSUSEU/ and Zenodo (link) Over the course of the project we have issued press releases, newsletters, promotional materials and peer reviewed publications (28 papers at the time of writing: https://www.colossusproject.eu/project-publications/) and presented on COLOSSUS at numerous conferences and events to reach our target audience.
There are currently limited treatment options once RAS mt mCRC tumours become resistant to standard therapy. Thus, there exists an urgent clinical need for a more personalised treatment paradigm in this setting. The fundamental objective of COLOSSUS has been 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 has delivered impact and progress beyond the state of the art across different key areas, including the following:

• We have established new subtypes for MSS RAS mt CRC patient stratification, advancing our knowledge of the condition and providing new avenues for further research.
• We have implemented an integrative systems modelling framework for the discovery of new methods for MSS RAS mt CRC patient stratification.
• We have established novel computational tools which have potential application to predict MSS RAS mt patient response.
• We have identified and tested promising new combinatorial treatment options for MSS RAS mt CRC patients with potential application across all COLOSSUS subtypes.
• We have developed new algorithms to identify pathway-based biomarkers for stratifying CRC subtypes.
• Our radiomics analysis has led to the identification of novel, non-invasive imaging biomarkers in mCRC.
• We have generated new commercialisation opportunities for partners GEX (pathway- and network-based predictions) and Veracyte (new biopharma Atlas).

As c.20% 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 any improvements to patient treatment would primarily be experienced by patients themselves (with improved outcomes and quality of life). Families, carers, social networks, clinicians and healthcare systems also stand to benefit, with potential ‘knock-on’ impacts for society as a whole. More effective treatments and a reduced burden of disease will facilitate greater contribution to the workforce and to society by patients and their support networks. Savings in healthcare costs realized through better and more effective mCRC treatments will mean more funding is available for other social assets. Reduced travel for treatment, reduced hospital time and avoidance of ineffective therapies will also yield energy savings and environmental benefits.

COLOSSUS has developed a novel approach to the classification of patients with MSS RAS mt mCRC, which will be further explored in future research. Importantly we have identified promising new combinatorial treatments for patients with MSS RAS mt mCRC with potential to apply across all COLOSSUS subtypes. Further study is needed but we believe our work has the potential to benefit patients and their families, clinicians and health care systems and deliver wider economic benefits.
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