Identification of cancer-specific kynurenine pathway profiles and their association with lifestyle factors and patient-reported outcomes – a focus on colorectal cancer

• Applicant: Professor Dr. Philipp Zimmer
• Subject Area: Gastroenterology ; Hematology, Oncology ; Metabolism, Biochemistry and Genetics of Microorganisms
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 577934577

The kynurenine pathway (KP) serves as the primary degrading route for tryptophan metabolism, leading to the production of several metabolites that possess immunomodulatory and neuroactive properties and regulate numerous physiological functions. Overactivation of the KP is implicated in many chronic diseases, including various types of cancer, by promoting an immunosuppressive microenvironment and potentially prolonging the survival of cancer cells. In colorectal cancer, previous work demonstrated strong associations between single kynurenine metabolites and poor prognosis as well as disease-related symptoms, including fatigue and reduced quality of life. However, research has primarily focused on single metabolites rather than overall disease-specific KP profiles. Objective 1 aims to identify comprehensive KP profiles in a large cohort of 609 colorectal cancer patients. The main data source for the proposed project is the “Energy for life after ColoRecal cancer (EnCoRe) study”, an ongoing prospective cohort study in the Netherlands. In addition, kynurenine metabolites from a breast cancer cohort consisting of 357 individuals and 141 healthy controls will be utilized for pan-cancer comparison. Blood analyses for KP metabolites have already been carried out for these cohorts, except for 30 newly assessed healthy individuals. Of note all samples have and will be analysed using the identical targeted metabolomics pipeline. Objective 2 investigates how lifestyle factors, which have directly been linked to colorectal cancer—including physical activity, diet and smoking habits —affect these KP profiles. Previous research indicates that engaging in regular physical activity can shift the KP towards a more neuroprotective and anti-inflammatory state, e.g. by increasing kynurenic acid levels. Similarly, healthy dietary patterns have been linked to positive effects on the KP in colorectal cancer survivors. Objective 3 aims to evaluate whether the identified KP profiles mediate the relationship between lifestyle factors and patient-reported outcomes such as depression and fatigue during a post-treatment period of six months. Epidemiological evidence shows that improved lifestyle factors – such as regular physical activity, a healthy diet and not smoking – reduce side effects of the disease and its treatment among colorectal cancer patients. However, the underlying biological mechanisms remain inadequately understood. In this context, the KP represents a promising link. Of note, all three objectives will be analysed back-to-back by classical statistical approaches as well as by AI based methods. The findings of this project will inform therapeutic and lifestyle strategies targeting the KP in order to improve prognosis and disease management among colorectal cancer patients.

• DFG Programme: Research Grants