We aim to develop and apply a suite of new technologies in a novel cancer discovery platform that will link high-definition cancer biology, via state-of-the-art disease imaging and pathway modelling, with development of novel interrogative and therapeutic interventions to test in models of cancer that closely resemble human disease. The work will lead to a new understanding of cancer invasion, how to treat advanced disease in the metastatic niche, how to monitor therapeutic responses and the compensatory mechanisms that cause acquired resistance. Platform development will be based on combined, cross-informing technologies that will enable us to predict optimal ‘maintenance therapies’ for metastatic disease by targeting cancer evolution and spread through combination therapy. A key strand of the platform is the development of quantitative multi-modal imaging in vivo by use of optical window technology to inform detailed understanding of disease and drug mechanisms and predictive capability of pathway biomarkers. Innovative methodologies are urgently needed to address declining approval rates of novel medicines and the unmet clinical needs of treating cancer patients in the advanced disease setting, where tumour spread and survival generally continues unchecked by current therapies. This work will be largely pre-clinical, but will always be mindful of the clinical problem in managing late stage human disease through rationale design of combination therapies with companion diagnostic tests. The cancer survival statistics will be changed if we can curb continuing spread of aggressive, metastatic disease and resistance to therapy by taking smarter combined approaches that make best use of emerging technologies in an innovative way, particularly where they are more predictive of clinical efficacy.