Reprogramming Epithelial WIRing to Eradicate CANcer (REWIRE-CAN)

About This Grant

RESEARCH ABSTRACT BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer death and increasingly affects young adults. Our team has recently made paradigm-shifting discoveries in CRC oncology, biology and signalling, while also establishing proof-of-concept for therapeutic reprogramming and hyperactivation-induced lethality, pioneered the development of the first direct oncogene activator and novel receptor-targeting strategies, with extensive expertise in translating basic research into drug development. Our proposal now unites two key concepts under a single cancer rewiring project: 1) Hyperactivation - Emerging data suggest that many cancer cells are susceptible not only to inhibition of oncogenic signaling - but also overactivation of these same pathways. In CRC the three major signaling pathways that are dysregulated (WNT, MAPK and PI3K) all show evidence for this ‘Goldilocks’ (‘just right’) phenomenon. Moreover, emerging preclinical candidate therapeutics are poised to, for the first time, exploit these newfound vulnerabilities. 2) Cell-state Rewiring - CRC is also notable for the diverse sets of cell-states that drastically modulate the response to clinical therapeutics and likely will influence both response to chemotherapy, targeted pathway inhibition and pathway activators. We are similarly poised to rewire these states to enhance the response to existing and emerging therapies. AIM: Develop clinically tractable strategies using signalling activators and inhibitors to destroy cancer cells via hyperactivation and rewire cancer cells towards vulnerable cell-states. APPROACH: REWIRE-CAN (Reprogramming Epithelial WIRing to Eradicate CANcer) will address this Cancer Grand Challenge by: - DISCOVERING novel agents to modulate and hyperactivate oncogenic pathways (WP1) - DEVELOPING approaches to use novel signalling activators to treat cancer via signalling hyperactivation and cell-state rewiring (WP2) - TRANSLATING therapeutic rewiring strategies into preclinical and clinical proof-of-concept studies (WP3) METHODS: REWIRE-CAN will combine functional analysis of patient samples with advanced drug discovery, including functional genetic screens, clinical bio-specimens, patient-derived organoids, animal models, and custom single-cell signalling technologies. This integrated approach will define combinatorial signalling dependencies in human CRC and allow us to directly translate these findings into in vivo therapeutic studies prior to clinical application. IMPACT: REWIRE-CAN will harness novel signal activators and the unique signalling biology of CRC to create a roadmap for sensitising cancer cells to therapy through signalling rewiring. Our lasting impact will be to identify novel therapeutics for advanced CRC, supported by in vivo proof- of-concept and tractability towards clinical candidate development. REWIRE-CAN will develop much- needed new therapies for CRC and also act as an exemplar for emerging signalling activator therapy in cancer.