The REDESIGN consortium proposes a multidisciplinary programme based on patient-derived organoids (PDOs) to guide personalised treatment in gastric cancer (GC) patients. Standard-of-care for locally advanced GC in Europe is neoadjuvant FLOT chemotherapy. Pathological response to neoadjuvant treatment is directly linked to overall survival. However, 63% of patients show resistance to the treatment and have no pathologic major response after treatment. Two different mechanisms are important in the aetiology of resistance: intra-tumoural heterogeneity and the accumulation of mutations that circumvent the point of action of a given drug. Deciphering intra-tumoural heterogeneity and predicting mutations that emerge under selective pressure of treatment will enable early identification of upcoming drug resistance, allowing tailored treatment strategies before the start of treatment.

We propose to integrate functional drug response data from PDOs from pre-and post-treatment specimens, dissecting clonal evolution and mutational adaptation of PDOs under selective treatment pressure, as well as CRISPR/Cas9 engineered human organoids. The consortium aims to unravel treatment resistance mechanisms and design treatment strategies that consider the identified causes of resistance. Further, the patient’s point of view will be taken into account in personalised treatment decisions. The overarching aim is to improve personalised treatment by combining the gained knowledge of evolutionary trajectories and mechanisms of resistance to therapy as well as addressing ethical and social challenges when using PDOs to aid clinical decision making in the era of precision medicine.