Searching for genetic vulnerabilities in osteosarcoma through genome-wide RNAi screening

An emerging concept in cancer drug discovery is that of genotype-specific drugs or drugs that only act in a cancer-specific genetic background.  Osteosarcoma, or bone cancer, is characterized by the deletion or mutation of two major cancer-associated genes called p53 and pRb.  We hypothesize that loss of p53 and pRb, in the human disease and in our mouse model of osteosarcoma, renders cancer cells particularly sensitive to inactivation of other genes or pathways that are less detrimental in non-cancerous cells. To test this hypothesis, we perturbed every gene in the mouse genome individually to identify genes that, when disrupted, selectively kill p53/pRb-mutant osteosarcoma cells. We have prioritized the list of genes that were identified in our screen and will now characterize and validate them in both mouse and human models of osteosarcoma in order to determine whether they represent bona fide therapeutic targets for the treatment of this devastating disease.