Rewiring oncogenic signalling to precision ablation of metastatic cancer

Abstract

Despite recent advances, long-term survival in metastatic carcinomas such as ovarian cancer remains limited by off-tumour toxicities of targeted therapies and low response rates to immunotherapy. Synthetic proteins have been engineered for selective recognition of oncogenic signalling states, but how they can be used to treat metastatic disease in vivo remains unclear. Addressing cancers driven by ErbB-family receptor tyrosine kinases such as EGFR and HER2, we used engineered proteins to restrict replication of a clinically approved viral backbone to kill cells with aberrant ErbB signalling. The resulting ErbB oncogene-selective virus (ErbB-OSV) showed superior safety to a benchmark oncolytic virus of the same family and superior efficacy against ErbB2/HER2-positive ovarian cancer xenografts. In a syngeneic model of advanced ovarian cancer, combining ErbB-OSV with chemotherapy and enabling repeated dosing by B cell depletion conferred a 180% larger survival benefit compared to chemotherapy alone, while single-agent ErbB-OSV cured most early cases. Thus, rationally restricting viral replication to ErbB-hyperactive cells with synthetic signalling proteins yields a highly specific therapeutic agent that ablates metastatic tumours in vivo more effectively than existing treatments.