Colorectal cancer (CRC) was diagnosed in 1.23 million people worldwide (EU 333,000) in 2008 and 608,000 (EU 148,000) died of the disease. While some new treatments have been advanced in CRC many have failed clinical testing; metastatic CRC is still largely incurable.In CRC, Cancer Stem Cells (CSC) are responsible for tumour progression and resistant to standard chemotherapies. The Wnt signal transduction cascade controls normal colon physiology but also CSC maintenance. Deregulation of Wnt and other mitogenic pathways results in formation of aggressive tumours with metastatic potential. Novel combinatorial drugs targeting CSCs are required to address signalling redundancy and subvert resistance and escape mechanisms. However to test them effectively better drug screening tools must be developed. The high failure rate in cancer drug research has been linked to the poor predictive capacity of drug screening models for cancer and the inability to select the right patients for treatment.In SUPPRESSTEM, novel antibody-based therapeutics will be designed to modulate the Wnt pathway externally in combination with mitogenic receptors resulting in specific inhibition of CSCs with minimal toxicity on healthy tissue. The likelihood of clinically translating these goals will be enhanced because testing will be performed on relevant human patient material (both tumour and normal) using organoid technology and novel imaging readouts. In depth analysis of the phenotype of responsive organoids (patient material) will be used to identify a lead product.Successful execution of SUPPRESSTEM will provide an innovative drug product and drug screening tool ready for clinical validation that ultimately will increase the life expectancy and quality of cancer patients. Funding of SUPPRESSTEM will enable three research-focused SME’s to establish an innovative drug discovery paradigm with broad application in the cancer drug development.