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Trialling new cancer therapies in those patients most likely to benefit

Stratifying patients based on the genetic profile of their tumour allowed researchers to target experimental therapies where they would have the maximum impact.

Health

Colorectal cancer (CRC) is the third most commonly occurring cancer in men, and the second most common in women. By 2030, global cases are expected to grow by 60 % to over 2.2 million cases and result in 1.1 million deaths. CRC is increasingly recognised as a heterogeneous disease: one which expresses itself differently from one patient to the next. It is thought to have distinct molecular subtypes, which have different biological processes at their core. This means the prognosis and most suitable treatments can also vary. The most common treatment, chemotherapy, comes with a wide range of detrimental impacts to the patient’s health. The EU-funded MoTriColor project developed a more targeted approach. Molecular diagnostic assessments on routine tumour biopsies identified distinct gene expression profiles with corresponding prognosis and drug response phenotypes, allowing therapies to be tailored to each patient. “Our overall objective was to develop new targeted therapeutic approaches for these specific molecular populations, that are potentially safer and more effective than currently available therapies,” explains Josep Tabernero, director of the Vall d’Hebron Institute of Oncology and head of the Medical Oncology Department at Vall d’Hebron University Hospital, Barcelona, Spain.

Patient-targeted trials

The primary objective of MoTriColor was to assess the safety and tolerability of experimental therapies, and their clinical efficacy – measured by reduction in tumour growth and spread, and patient survival rate. The project also checked for resistance to the treatments, and monitored the circulating tumour DNA (ctDNA) in the patient’s bloodstream. Crucially, patients were first stratified based on the gene expression profiles of their cancer, and matched the clinical trial that offered the most suitable treatment. As a result, Tabernero and his team were able to successfully validate a novel treatment approach with the combination of atezolizumab immunotherapy and bevacizumab, an antiangiogenic agent. “This represents an important clinical milestone, given the poor prognosis for this specific CRC patient cohort,” says Tabernero, MoTriColor project coordinator. The clinical and molecular data generated by these trials will allow the research team to identify patients who should respond best to this therapeutic approach. In addition, the project created a database profiling gene expression across patients with CRC. “We have identified tumour-associated mutations that can be used to monitor tumour burden during treatment by the liquid biopsy tracking ctDNA,” adds Tabernero.

Broader impacts

The results showed the team successfully set up technologies with a high impact on cancer immunotherapy, representing a breakthrough towards understanding tumour antigens recognised by the immune system of patients with colorectal cancer. This will be key to improving the outcome of immunotherapy not just in CRC patients, but also in other cancer patients receiving immunotherapy.

Keywords

MoTriColor, colorectal cancer, target, antigens, ctDNA

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