COLTHERES (the Colon Therapy Research Consortium) has revealed in its first interim report key results that will enable a more personalized and effective approach to be taken in treatment of colon cancer using two novel drugs; the EGFR inhibitor Cetuximab and the BRaf inhibitor Vemurafinib.
COLTHERES is a four year project, which was established with funding from the EU Framework-7 program, to uncover new genetic biomarkers that will predict which patients are most likely to respond to a range of new targeted therapies in colon cancer and whether the majority of patients who are resistant can be rendered sensitive again using specific drug combinations.
COLTHERES integrates experts in biomarker-driven clinical trials, genomics, functional genomics, and isogenic disease model generation using rAAV-mediated genome editing, to comprehensively identify, validate and translate new candidate biomarkers of drug response and novel drug combinations into the clinical setting.
The key findings detailed in the interim report were:
• Identification of biomarkers in patients resistant to EGFR targeted therapies, to enable a more personalized approach to therapy
Building on seminal founding studies by members of the COLTHERES consortium, which showed that activating mutations in KRAS are the cause of resistance to EGFR-inhibitors in 30-40% of colon cancer patients, the consortium has now identified additional biomarkers in a further 30-40% of patients who are resistant to Cetuximab.
These include mutations in key downstream molecules, over-expression of activating or competing molecules, or loss of pathway inhibitors which, when combined with a global gene expression signature also developed by the team, will form a far more comprehensive ability to identify responders to Cetuximab treatment than by KRAS mutations alone.
• Molecular evidence to support an alternative therapeutic approach for BRAF mutant patients
The consortium has also identified why some BRAF mutant colon cancer patients, in stark contrast to melanoma patients, are unresponsive to Vemurafenib therapy (an inhibitor of BRAF). In this case, a rapid feedback activation of the EGFR receptor was found in colon cancers that are being treated with Vemurafinib, which opens up the possibility that a targeted combination of an EGFR-inhibitor and Vemurafinib may now allow a robust response in these patients. In vitro and preclinical data are encouraging in this regard and a clinical trial is now the planning stages.
• Validation of a new diagnostic technique for early prediction of patient relapse
A cutting-edge diagnostic technique called ‘BEAMing’ has been used by the Consortium to monitor and analyze tumor DNA over time in the blood of patients who are initially responsive to treatment, enabling the detection of secondary ‘acquired’ mutations in the KRAS gene that are causally associated with acquired resistance to targeted therapies for colorectal cancer.
As these mutations can be detected using simple non-invasive liquid biopsies, and critically several months before radiographic evidence of disease progression is observable, clinicians can anticipate and counter resistance using targeted drug combinations before the patient relapses.
Prof. Alberto Bardelli, IRCC University of Torino, co-founder Horizon Discovery Ltd and Lead Investigator of COLTHERES, said: “In its first 18 months COLTHERES has exceeded our expectations; defining new molecular markers leading to personalized therapies for colorectal cancer patients and providing data for use as the basis of innovative clinical trials. The expertise and technologies offered by the consortium members have made this possible, and we anticipate further breakthroughs in the remainder of the project term.”
Members of the COLTHERES consortium have jointly authored a number of publications in high profile journals such as Nature over the first 18 months of the program, and results have been presented at international meetings such as AACR, ESMO and ASCO.