RESEARCH Focus

Colossus

The overarching aim of the EU funded H2020 programme Colossus is to develop new stratification tools for Kras mutant microsatellite stable metastatic colorectal cancer (mCRC) in a multi-‘omic integrative approach. Currently, in other stratification systems (Guinney et a Nat Med, 21 (11), 1350-6 2015; Smeets, Miller O’ Connor et al Nat Commun, 9 (1), 4112 2018), Kras mutant mCRC is not stratified into one particular subtype. Therefore, new specific Kras mutant subtypes are urgently needed. An additional aim is identify key targetable vulnerabilities within the new subtypes to test novel combinations of therapies and improve outcomes in this hard-to treat subtype of ,CRC. Specifically in our group we are tasked with developing state-of-the-art orthotopic models of Kras mutant CRC, to facilitate the testing of these novel combination therapies. In light of this, we have developed a Patient derived xenograft (PDX) intracaecal implantation model of Kras mutant CRC. Furthermore, we implemented a robust contrast enhanced µCT-imaging platform to monitor and analyse the PDX tumours.

EDiREX

The overall goal of EDIReX is to establish a cutting-edge European infrastructure offering Trans-national Access (TA) of PDX resources to academic and industrial cancer researchers, including the distribution of cryopreserved samples to third parties, the structured biobanking of user-developed models, and the performance of efficacy studies. In order to provide robust and high quality PDX material to third parties, the PDXs need to be well characterized. As such within the Edirex framework, each PDX will have a unique “PDX passport”, a highly detailed document that outlines several key factors of the PDX eg:

1. Growth rate

2. Response to standard of care drugs in both the subcutaneous and orthotopic setting

3. Detailed imaging analyses  (PET, µCT and MRI)

4. Genomic analyses

Here within the PCM group using the state of the art orthotopic model CRC, we specifically investigate how Kras wild type CRC tumours respond to standard of care cetuximab. The models will be followed with a rigorous µCT imaging protocol. These data will be compared to results from other sites who are characterising the same PDX tumours. This multi-centre testing will ensure robust characterisation of each PDX and ensuring high quality tissue will be delivered to 3rd parties thought the TA process.

Radcol

The overall goal of the HEA funded RADCOL project is to develop radiomic signatures which can be used for the early detection of colorectal cancer liver metastasis and post treatment disease recurrence. To achieve this we will use a process know as radionics to extract features from CT images. These features will then be used to generate radiomic signatures which can be used to identify patients who are treatment responders or non responders earlier than is possible from imaging alone

Cell Free dna liquid biopsy assay

Current treatment for KRAS mutant mCRC is based on 5-fluoruracil (5-FU) combinations +/- the anti-angiogenesis agent bevacizumab (BVZ). Previously we have described a new classification system (based on copy number alterations (CNA) patterns) to predict mCRC patient response to SOC chemotherapy + BVZ and have recently published our findings (Smeets, Miller O’ Connor et al Nat Commun, 9 (1), 4112 2018). Specifically, tumours belonging to intermediate-to-high instability clusters have improved outcome following chemotherapy plus BVZ versus chemotherapy alone. In contrast, low instability tumours, which amongst others consist of POLE-mutated and microsatellite instable tumors, derive no further benefit from BVZ. Overall, we have identified copy number load as a novel potential predictive biomarker of BVZ combination therapy. As part of the HRB funded Liquid biopsy project, we are now developing a non-invasive plasma-derived cell-free DNA (cfDNA) diagnostic assay to support the clinical translation of our newly discovered classifiers to predict BVZ response in mCRC. Such a blood-based test is important, as most mCRC patients do not undergo a secondary biopsy. Instead, only the initial diagnostic biopsy of an earlier CRC (often taken several years prior) is available, and the molecular tumour phenotype may have changed over time. We are therefore developing and validate a non-invasive plasma-derived cfDNA diagnostic assay utilising low coverage whole genome sequencing. We will confirm CNA profiles found in plasma are concordant with CNA profiles found in the matched patient tumour.  The liquid biopsy assay will be used to stratify and predict which patients will gain benefit from BVZ + SOC chemotherapy