Advancing personalised metastatic colorectal cancer therapy

LIH researchers develop functional profiling approach to predict response to treatment

• Personalized Functional Profiling (PFP)
• Luxembourg Research Clinic – Fuerschungsklinik Lëtzebuerg
• Translational Medicine Operations Hub (TMOH)

In a new study, scientists at the Luxembourg Institute of Health (LIH), in collaboration with the Laboratoire National de Santé (LNS) and the Hôpitaux Robert Schuman (HRS), describe an innovative approach based on screening anticancer drugs directly on patient-derived tumour models, which could help predict treatment responses in metastatic colorectal cancer (mCRC) and pave the way towards more personalised and effective patient care. The paper was published in the prestigious Nature Portfolio journal “npj Precision Oncology”.

Colorectal cancer is the third most commonly diagnosed cancer worldwide and the second leading cause of cancer-related deaths. While survival rates have improved thanks to advances in screening and treatment, outcomes remain poor for patients with metastatic disease, with five-year survival rates below 15%. Current treatment decisions rely heavily on genomic analyses that identify mutations in tumours. However, genetic data alone often fails to predict whether a therapy will actually work for a patient. Moreover, resistance to currently available anticancer agents remains a major treatment challenge. Therefore, the development of effective therapeutic approaches to fight mCRC represents an urgent medical need.

To address this challenge, Drs Victoria El-Khoury and Yong-Jun Kwon from the Precision Medicine Technology group at the Luxembourg Institute of Health (LIH) developed a drug-screening platform using patient-derived spheroids (PDS), three-dimensional tumour models grown from patients’ cancer cells that closely mimic the genetic features of the original tumour, allowing scientists to observe how an individual patient’s tumour reacts to different treatments.

Specifically, the research team generated spheroids from tumours derived from twelve patients with metastatic colorectal cancer and tested them against 42 anticancer drugs as well as standard-of-care therapies, both individually and in combinations. The results showed that the screening approach successfully distinguished patients who were likely to respond to anti-EGFR therapies, a commonly used targeted treatment in colorectal cancer, from those who were resistant. In several cases, the platform also revealed potential alternative therapeutic opportunities, including sensitivity to drugs targeting ERBB2 or ERBB3 signaling pathways. At the same time, responses to standard chemotherapy varied widely between patients, reflecting the biological heterogeneity of metastatic colorectal cancer. Importantly, in several instances the drug responses observed in the laboratory mirrored the clinical responses seen in patients, highlighting the predictive potential of the method.

Genomic profiling has transformed precision oncology, but it does not always tell us which therapy will work best for a given patient. By directly testing drugs on tumour cells grown from patients, we showed that functional profiling can reveal vulnerabilities that genomic data alone might miss and help guide more informed treatment strategies

explains Dr El-Khoury,  first author of the study.

The findings also illustrate how functional drug testing can complement genetic sequencing to provide a more comprehensive picture of tumour behaviour. Notably, functional profiling can accurately predict clinical outcomes in cases where genomic data alone would suggest a different response, such as the resistance to dual BRAF/EGFR-targeted therapy in a BRAF-mutant case. Conversely, some treatments, particularly anti-angiogenic drugs targeting VEGFR, did not show activity in the spheroid models, highlighting the limitations of in vitro systems that lack elements of the tumour microenvironment such as blood vessels.

Another important aspect of the study was assessing whether this approach could be implemented within clinically meaningful timelines. The researchers demonstrated that drug screening results could be generated within approximately six weeks after tumour sampling, a timeframe comparable to other emerging functional precision oncology platforms.

Our goal is to develop practical tools that help clinicians match patients with the most effective therapies as quickly as possible. Functional profiling using patient-derived tumour models offers a promising path toward that objective, especially when combined with genomic data

says Dr Kwon, last author of the study.

While the results provide a strong proof of concept, further validation in larger patient cohorts will be needed before the approach can be integrated into routine clinical practice. Future work will focus on refining the drug panels to reduce turnaround time and on developing more advanced tumour models that incorporate components of the tumour microenvironment. By combining patient-derived models, high-throughput drug screening and genomic analysis, researchers at the LIH aim to move closer to truly personalised treatment strategies for metastatic colorectal cancer and improve outcomes for patients facing limited therapeutic options.

This work was funded by the Ministry of Research and Higher Education (MESR) under the Personalised Functional Profiling (PFP) programme, and by the Luxembourg National Research Fund (FNR) through the INTER/ANR/21/15853435 and the  PEARL P16/BM/11192868 grants. The “Fondation Hôpitaux Robert Schuman” (FHRS) supported this project by funding the equipment and the research laboratory at the clinical site.

The study was published in March 2026 with the full title “Predicting therapeutic responses in metastatic colorectal cancer through personalized functional profiling of patient-derived spheroids”.